AU2016317968B2 - Compound having effect of inhibiting platelet aggregation and salt thereof, and composition for preventing or treating thrombotic diseases, containing same - Google Patents

Compound having effect of inhibiting platelet aggregation and salt thereof, and composition for preventing or treating thrombotic diseases, containing same Download PDF

Info

Publication number
AU2016317968B2
AU2016317968B2 AU2016317968A AU2016317968A AU2016317968B2 AU 2016317968 B2 AU2016317968 B2 AU 2016317968B2 AU 2016317968 A AU2016317968 A AU 2016317968A AU 2016317968 A AU2016317968 A AU 2016317968A AU 2016317968 B2 AU2016317968 B2 AU 2016317968B2
Authority
AU
Australia
Prior art keywords
added
methanone
hydroxy
mixture
methyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Active
Application number
AU2016317968A
Other versions
AU2016317968A1 (en
Inventor
Geum Sil CHO
Jin Ho Chung
Dong Won Lee
Jae Young Lee
Kang Hyeok Lee
Ki Sung Lee
Jin Hun Park
Woo Ile PARK
Jei Man Ryu
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Shin Poong Pharmaceutical Co Ltd
Original Assignee
Shin Poong Pharmaceutical Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Shin Poong Pharmaceutical Co Ltd filed Critical Shin Poong Pharmaceutical Co Ltd
Publication of AU2016317968A1 publication Critical patent/AU2016317968A1/en
Application granted granted Critical
Publication of AU2016317968B2 publication Critical patent/AU2016317968B2/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/423—Oxazoles condensed with carbocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4365—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system having sulfur as a ring hetero atom, e.g. ticlopidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C235/46—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C235/48—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring having the nitrogen atom of at least one of the carboxamide groups bound to an acyclic carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C235/56—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/56—Amides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/65—One oxygen atom attached in position 3 or 5
    • C07D213/66—One oxygen atom attached in position 3 or 5 having in position 3 an oxygen atom and in each of the positions 4 and 5 a carbon atom bound to an oxygen, sulphur, or nitrogen atom, e.g. pyridoxal
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D231/38—Nitrogen atoms
    • C07D231/40—Acylated on said nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/20—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/06—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by halogen atoms or nitro radicals
    • C07D295/073—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by halogen atoms or nitro radicals with the ring nitrogen atoms and the substituents separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
    • C07D295/182—Radicals derived from carboxylic acids
    • C07D295/192—Radicals derived from carboxylic acids from aromatic carboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/34—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D309/36—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with oxygen atoms directly attached to ring carbon atoms
    • C07D309/38—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with oxygen atoms directly attached to ring carbon atoms one oxygen atom in position 2 or 4, e.g. pyrones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/24—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D333/30—Hetero atoms other than halogen
    • C07D333/36—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Hematology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Diabetes (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pyridine Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Heterocyclic Compounds Containing Sulfur Atoms (AREA)
  • Pyrane Compounds (AREA)
  • Indole Compounds (AREA)

Abstract

The present invention relates to a novel compound having an effect of inhibiting platelet aggregation and a salt thereof and, more specifically, to: a novel platelet aggregation inhibitor specifically inhibiting shear stress-induced platelet aggregation; a pharmaceutical composition containing the same as an active ingredient; and a preparation method therefor.

Description

HELVETICA CHIMICA ACTA, (2009-06-01), vol. 92, no. 6, pages 1126 - 1133 YU K-L ET AL, "Novel quinolizidine salicylamide influenza fusion inhibitors", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, (1999-08-02), vol. 9, no. 15, pages 2177 - 2180 SCHUBERT H ET AL, "SYNTHESE UND OXYDATION VON UNSYMMETRISCH VERBRUECKTEN DIHYDROCHINONEN", JOURNAL FOR PRAKTISCHE CHEMIE (1977-01-01), vol. 319, no. 5, pages 745 - 754 US 2899437 A WO 2005/13489 Al HUDSON, R.A., et. al., Simplified Catechin-Gallate Inhibitors of HIV-1 Reverse Transcriptase, Bioorganic & Medicinal Chemistry Letters (2001), Volume 11, issue , pages 2763-2767 WO 2010/023161 Al WO 2015/50379 Al CAS Registry Number 1204951-11-0, STN entry date 09 February 2010 CAS Registry Number 1789948-21-5, STN entry date 28 June 2015 CAS Registry Number 1638343-39-1, STN entry date 10 December 2014 CAS Registry Number 1205211-63-7, STN entry date 10 February 2010 Cas Registry Number 1790098-32-6, STN entry date 28 June 2015 WO 2014/118361 Al WASSIER, K., et. al., Synthesis and antifungal evaluation of hydroxy-3 phenyl-2H-1,3-benzoxazine-2,4(3H)-diones and their thioanalogs, Journal of Heterocyclic Chemistry (2009), Volume 46, Issue 5, pages 873-880 CAS Registry Number 1690723-58-0, STN entry date 25 April 2015 CAS Registry Number 1049136-81-3, STN entry date 14 September 2008 PAN, S., et al., "Synthesis and biological activity of tyrosine protein kinase inhibitors", Acta Pharmaceutica Sinica, (1997), Volume 32, Issue 7, pages 515-523 WO 2012155812 Al CAS Registry Number 1204953-50-3, STN entry date 09 Feb 2010 CAS Registry Number 1309259-73-1, STN entry date 13 Jun 2011 CAS Registry Number 1205860-99-6, STN entry date 11 Feb 2010 CAS Registry Number 1789283-42-6, STN entry date 26 Jun 2015 CAS Registry Number 1205502-72-2, STN entry date 10 Feb 2010 CAS Registry Number 1789654-44-9, STN entry date 26 Jun 2015 CAS Registry Number 1205501-86-5, STN entry date 10 Feb 2010 CAS Registry Number 1205471-73-3, STN entry datelO Feb 2010 CAS Registry Number 1205469-73-3, STN entry date 10 Feb 2010 CAS Registry Number 1204918-08-0, STN entry date 09 Feb 2010 CAS Registry Number 1204916-56-2, STN entry date 09 Feb 2010 CAS Registry Number 1030528-04-1, STN entry date 25 Jun 2008 CAS Registry Number 328011-42-3, STN entry date 19 Mar 2001 CAS Registry Number 1789287-05-3, STN entry date 26 Jun 2015 CAS Registry Number 1787735-48-1, STN entry date24 Jun 2015 CAS Registry Number 1786146-62-0, STN entry date 22 Jun 2015 CAS Registry Number 1786146-72-2, STN entry date 22 Jun 2015 ZHANG, H., ET AL., "Lamiridosins, Hepatitis C Virus Entry Inhibitors form Lamium album" J. Nat. Prod. (2009), Volume 72, pages 2158-2162 LI, X. H., ET AL, "A new phenolic lactone from the bark of Phellodendron chinese", Chinese Chem. Lett., (2009), Volume 20, pages 958-960 WANG, H., ET AL, "Chemical Studies on Iridoids form Picrorhiza scrophulariiflora", Chin. J. Nat. Med., (2006), Volume 4, Issue 1, pages 36-39 WO 2017/019772 Al EP 0251143 Al US 5523421 Al
(10) Al1A7X 72 (4 3) q;A - 1 '' 70 -2adY71V 2017 'A 3 9 Op (09.03.2017) W IPO | P C T WO 2017/039395 Al
(51) ¶xlI$le-: Young); 16843 471 -9-1 T1A] V 52,5804 C07D 495/04 (2006.01) A61K31/4365 (2006.01) -- 1203, Gyeonggi-do(KR). C7D61/2(200.01 120331/423(2006.01) C07D 261/20 (2006.01) A61K31/423 (2006.01) (74) 1j el t1: 41M 1il (HANSUNG INTELLECTUAL C07D 413/04 (2006.01) A61K31/5375 (2006.01) PROPERTY); 06233 ^2 RA] 7 Ti 7 4 _V 84 (21) X: ); PCT/KR2016/009859 23, 4, Seoul (KR). (22) -x : 2016 9 V 2 0(02.09.2016) (81) Al;9 a 7(- A7} o t, 7} 2 E §l4 (25) 06.ol,1 6I M 99 - 9 - 0° ): AE, AG, AL, AM, AO, -°1 AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, (26) &7101 6: 1 CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, DZ, EC, EE, EG, ES, Fl, GB, GD, GE, GH, GM, GT, HN, (30) 1: HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KZ, LA, 10-2015-0125270 2015 ' 9-V 4 (04.09.2015) KR LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, MK, MN, (71) * V t1: 414l 9 X1 A A} (SHIN POONG PHAR- MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PA, PE, MACEUTICAL CO., LTD.) [KR/KR]; 15610 771]O1 PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, SD, SE, S T ^ 7, Gyeonggi-do (KR). SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (72) i¶7}: $1,71 (RYU, Jei Man); 14045 4 71 00A] T Al L V 159 - 58, 207 101 , Gyeonggi- (8- 7 0 do (KR). 01 -t (LEE, Dong Won); 15866 4 71 _' 44 N L Lu _V_ °r1 0° ): ARIPO (BW, GH, GM, 1]de MN34, 640 606 9, Gyeonggi-do (KR). 017d KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, TZ, UG, S(LEE, Kang Hyeok); 18476 471 6}^-o^1 A ZM, ZW), T4 A] 4} (AM, AZ, BY, KG, KZ, RU, TJ, 1 A]9 122, 1467~ 1402 , Gyeonggi-do(KR).V TM), - , (AL, AT, BE, BG, CH, CY, CZ, DE, DK, EE, (PARK, Jin Hun); 22704 l] Al7 53, 113 ES, Fl, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, MC, 404 , Incheon (KR).4 (CHO, Geum Sil). MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, TR), 401747 ^-Fi] Ii k^1 ( M T - 18 19, 204G 801 OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, KM, Seoul (KR). 0171-V (LEE, Ki Sung); 18109 771 ML,MR, NE,SN, TD,TG). A] O1711l 60, 513 1401 9, Gyeonggi-do (KR). &71: - (CHUNG, Jin Ho); 06519,A1rA I I 1 4 - 1^} 1- (& °]]21 3)) -733-9, 347 806 9, Seoul (KR). +-(PARK, Woo Ile); 14074 71]- i@^1 -- l _V_101,104 1102 9 , Gyeonggi-do (KR). 01 Al ¶ (LEE, Jae
(54) Title: COMPOUND HAVING EFFECT OF INHIBITING PLATELET AGGREGATION AND SALT THEREOF, AND COMPOSITION FOR PREVENTING OR TREATING THROMBOTIC DISEASES, CONTAINING SAME
(57) Abstract: The present invention relates to a novel compound having an effect of inhibiting platelet aggregation and a salt there of and, more specifically, to: a novel platelet aggregation inhibitor specifically inhibiting shear stress-induced platelet aggregation; a pharmaceutical composition containing the same as an active ingredient; and a preparation method therefor.
(5 7) A 4 -o- ?% (estress-induced pal ti Ad 1 0, Al 01 3-1 ^, le _0 ?V_ %, AJ- A}1
[Specification]
[Title of the Invention]
COMPOUND HAVING EFFECT OF INHIBITING PLATELET AGGREGATION AND SALT THEREOF, AND COMPOSITION FOR PREVENTING OR TREATING THROMBOTIC DISEASES, CONTAINING SAME
[Field of the Invention]
The present invention relates to a new compound having inhibitory effect for platelet
aggregation and a salt thereof. More specifically, the present invention relates to a new
platelet aggregation inhibitor that can selectively inhibit shear stress-induced platelet
aggregation; a pharmaceutical composition comprising the same as an active ingredient; and
a process for preparing the same.
[Background]
The human body has a self-healing or defensive system for healing and prevention of
loss of blood at wound sites, which is achieved by modulation and balancing among clotting
of platelets and plasma, degradation of fibrin, and inhibition of coagulation. When these
proper control and balance are disturbed by various factors, abnormal platelet aggregation
occurs and that leads to thrombotic diseases.
Thrombosis refers to a condition wherein the blood circulation system is disturbed by
a blood clot in the blood vessel, or in the worst case, the flow of blood is blocked.
Thrombosis may cause atherothrombosis, phlebothrombosis, hepatic portal vein thrombosis,
pulmonary thromboembolism, chronic limb ischemia, varicose veins, deep vein thrombosis
diseases, angina pectoris, cerebral infarction, cerebral hemorrhage, and the like, and it may
also contribute to infection, vascular injury, postoperative complications, coagulative diseases,
and the like. Such thrombosis can be generated by interaction among abnormal blood vessel
walls, hemodynamic forces, coagulation proteins in the plasma, and platelets. Platelets are
activated by various agonists such as adenosine diphosphate, thromboxane A 2, and thrombin,
and the activated platelet glycoproteins such as Ilb/Ila are combined with aggregation
proteins in the blood (fibrinogen, von Willebrand factor, etc.) to cause an aggregation
reaction.
Recently, it has been known that platelets are abnormally activated not only by
chemical agonists but also by physical stimulation, resulting in thrombosis. Among the
physical stimuli, shear stress is the most influential factor in platelet activation. Shear stress
refers to the force of the bloodstream on the cells within the blood vessels, such as platelets,
red blood cells and endothelial cells. An abnormal change in shear stress is the major cause
of pathologic arterial thromboli development in vivo, which is caused by artery dissection
due to percutaneous coronary intervention such as stent, atherectomy, and balloon
angioplasty; vascular spasm; or diseases such as hypertension and atherosclerosis.
When the shear stress increases abnormally, platelets are activated, and the
glycoproteins Ilb/Ila of the activated platelets directly bind to von Willebrand factor,
resulting in aggregation. These phenomena accelerate the signaling pathway in platelets,
increase intracellular calcium concentration, and induce the release of various activating factors from granules, thereby promoting platelet aggregation and producing thrombosis
(Nesbitt et al., Nature Medicine 15, 665 - 673 (2009)).
The currently used agents for the prevention and treatment of thrombotic diseases
include antiplatelet agents that antagonize chemical agonists (e.g., aspirin, clopidogrel, etc.),
anticoagulants (e.g., heparin, warfarin, etc.), thrombolytic agents for treating preformed
thrombli (e.g., tissue plasminogen activator, etc.), and so on. Aspirin is known to cause side
effects such as gastrointestinal bleeding and peptic ulcer, although it is fairly effective.
Most of the other anticoagulants cannot be orally administered and exhibit various side
effects after prolonged administration such as hemorrhage, hemolysis, immune reaction,
fever and allergy, because of their low selectivity for thrombosis. In addition to these side
effects and ineffectiveness, there is another problem of prohibitively expensive prices of
some commercially available therapeutic agents.
For the above reasons, there is a need to develop an antiplatelet agent that selectively
affects shear stress-induced platelet aggregation and has few side effects (Kiefer and Becker,
Circulation, 2009, 120:2488-2495/Gilbert et al., Circulation, 2007, 116:2678-2686).
[Disclosure of the Invention]
[Problem to be solved]
The present invention is based on the finding that certain compounds having amide
and ester structures that are obtained through the structure activity relationship study of
platelet aggregation inhibition are useful for prevention or treatment of thrombotic diseases
while having few side effects such as bleeding.
[Means to solve the problem]
In a first aspect of the invention there is provided a compound, which is selected from the
following group:
(6,7-Dihydrothieno[3,2-c]pyridin-5(4H)-yl)(3,4-dihydroxypheny)methanone;
(3,4-Dihydroxyphenyl)(4-(5-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)methanone;
N-((4-(4-Fluorobenzyl)morpholin-2-yl)methyl)-3,4-dihydroxybenzamide;
3,4-Dihydroxy-N-(2-oxotetrahydrothiophen-3-yl)benzamide;
N,N'-(Nonan-1,9-diyl)bis(3,4-dihydroxybenzamide);
(4-((4-Chlorophenyl)(pyridin-2-yl)methoxy)piperidin-1-yl)(3,4
dihydroxyphenyl)methanone;
(S)-(4-((4-Chlorophenyl)(pyridin-2-yl)methoxy)piperidin-1-yl)(3,4
dihydroxyphenyl)methanone;
(S)-Methyl-2-(3,4-dihydroxybenzamido)-3-(1H-indol-3-yl)propanoate;
4-(3,4-Dihydroxybenzamido)-1-methyl-3-propyl-1H-pyrazole-5-carboxamide;
2-Methyl-4-oxo-4H-pyran-3-yl 3,4-dihydroxybenzoate;
(3,4-Dihydroxyphenyl)(4-phenylpiperazin-1-yl)methanone;
(6,7-Dihydrothieno[3,2-c]pyridin-5(4H)-yl)(4-hydroxy-3
methoxyphenyl)methanone;
2-Ethyl-4-oxo-4H-pyran-3-yl 4-hydroxy-3-methoxybenzoate;
2-Methyl-4-oxo-4H-pyran-3-yl 4-hydroxy-3-methoxybenzoate;
4-Hydroxy-3-methoxy-N-(4-methoxy-2-nitrophenyl)benzamide;
4-(4-(4-Hydroxy-3-methoxybenzamido)phenoxy)-N-methylpicolinamide;
4-((4-Chlorophenyl)(pyridin-2-yl)methoxy)piperidin-1-yl)(4-hydroxy-3
methoxyphenyl)methanone;
(27029751_1):AXG
4a
4-Hydroxy-N-((3-hydroxy-5-(hydroxymethyl)-2-methylpyridin-4-yl)methyl)-3
methoxybenzamide;
(6,7-Dihydrothieno[3,2-c]pyridin-5(4H)-yl)(2,5-dihydroxyphenyl)methanone;
(4-((4-Chlorophenyl)(pyridin-2-yl)methoxy)piperidin-1-yl)(2,5
dihydroxyphenyl)methanone;
N-((4-(4-Fluorobenzyl)morpholin-2-yl)methyl)-2,5-dihydroxybenzamide;
(2,5-Dihydroxyphenyl)(4-(5-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)methanone;
N-(3,4-Dimethoxyphenethyl)-2,5-dihydroxybenzamide;
2,5-Dihydroxy-N-(2-(thiophen-2-yl)ethyl)benzamide; and
2,5-Dihydroxy-N-(2-oxotetrahydrothiophen-3-yl)benzamide,
or a pharmaceutically acceptable salt or stereoisomer thereof
In a second aspect of the invention, there is provided a composition for the
prevention or treatment of thrombotic diseases, comprising as an active ingredient a
compound according to the first aspect of the invention, or a pharmaceutically acceptable salt
or stereoisomer thereof.
In a third aspect of the invention, there is provided a method of prevention or
treatment of thrombotic diseases associated with shear stress-induced platelet aggregation in
a subject in need thereof, the method comprising administering to the subject a
therapeutically effective amount of a compound of the first aspect of the invention or a
pharmaceutically acceptable salt or stereoisomer thereof.
In a fourth aspect of the invention, there is provided a use of a compound of the first
aspect of the invention or a pharmaceutically acceptable salt or stereoisomer thereof in the
manufacture of a medicament for prevention or treatment of thrombotic diseases associated
with shear stress-induced platelet aggregation in a subject in need thereof.
(27029751_1):AXG
4b
A further aspect of the present invention relates to a compound represented by the
following Formula (I) or (II), or a pharmaceutically acceptable salt or isomer thereof:
[Formula I]
0
X R2
HO R,
[Formula II]
0 HO N R2
OH
wherein,
R' is hydroxy or C1 -C1 0 alkoxy;
X is N or 0;
R2 is -(CH2)p-5- to 12-membered heterocycle-(CH2)p-C6-C12 aryl, 5- to 12-membered
heterocycle, -(CH2)p-NHC(=O)-C6-C12 aryl, -CHR 4 R5 , 5- to 12-membered heteroaryl, C6-C12
aryl, -C 6 -C 12 aryl-O-5- to 12-membered heteroaryl, -(CH2)p-5- to 12-membered heteroaryl, or
-(CH2)p-C6-C12 aryl,
(27029751_1):AXG wherein p is an integer of 1 to 10; R4 and R5 are each independently C 1 -C6 alkoxycarbonyl or -CH 2-5- to 12-membered heteroaryl; said heterocycle and heteroaryl may contain 1 to 3 heteroatoms selected from N, 0, and S; and said heterocycle, heteroaryl, and aryl can be substituted with 1 to 4 substituents selected from the group consisting of halogen, oxo, aminocarbonyl, C 1-C 6 alkyl, nitro, C-C6 alkoxy, nitrile, C-C6 alkylaminocarbonyl, hydroxy, and hydroxy-CI-C 6 alkyl;
R3 is hydrogen;
when X is 0, R3 does not exist;
when X is N, X taken together with R2 and R3 may form a 5- to 12-membered
heterocycle containing 1 to 3 heteroatoms selected from 0, N and S; wherein said heterocycle
can be substituted with C6 -CI2 aryl; a 6- to 12-membered heteroaryl containing 1 to 3
heteroatoms selected from 0, N and S, which is unsubstituted or substituted with halogen; or
-0-CHR6R7; and wherein R6 and R7 are each independently C-C 21 aryl or a 6- to 10
membered heteroaryl containing 1to 3 heteroatoms selected from N, 0 and S, both of which
are unsubstituted or substituted with halogen.
Specific examples of the compounds are as follows:
1. (6,7-Dihydrothieno[3,2-c]pyridin-5(4H)-yl)(3,4-dihydroxyphenyl)methanone
2. (3,4-Dihydroxyphenyl)(4-(5-fluorobenzo[d]isoxazol-3-yl)piperidin-1
yl)methanone
3. N-((4-(4-Fluorobenzyl)morpholin-2-yl)methyl)-3,4-dihydroxybenzamide
4. 3,4-Dihydroxy-N-(2-oxotetrahydrothiophen-3-yl)benzamide
5. N,N'-(Nonan-1,9-diyl)bis(3,4-dihydroxybenzamide)
6. (4-((4-Chlorophenyl)(pyridin-2-yl)methoxy)piperidin-1-yl)(3,4
dihydroxyphenyl)methanone
7. (S)-(4-((4-Chlorophenyl)(pyridin-2-yl)methoxy)piperidin-1-yl)(3,4
dihydroxyphenyl)methanone
8. (S)-Methyl-2-(3,4-dihydroxybenzamido)-3-(1H-indol-3-yl)propanoate
9. 4-(3,4-Dihydroxybenzamido)-1-methyl-3-propyl-1H-pyrazole-5-carboxamide
10. 2-Methyl-4-oxo-4H-pyran-3-yl 3,4-dihydroxybenzoate
11. (3,4-Dihydroxyphenyl)(4-phenylpiperazin-1-yl)methanone
12. (6,7-Dihydrothieno[3,2-c]pyridin-5(4H)-yl)(4-hydroxy-3
methoxyphenyl)methanone
13. 2-Ethyl-4-oxo-4H-pyran-3-yl 4-hydroxy-3-methoxybenzoate
14. 2-Methyl-4-oxo-4H-pyran-3-yl 4-hydroxy-3-methoxybenzoate
15. 4-Hydroxy-3-methoxy-N-(4-methoxy-2-nitrophenyl)benzamide
16. N-(3-Ethynylphenyl)-4-hydroxy-3-methoxybenzamide
17. 4-(4-(4-Hydroxy-3-methoxybenzamido)phenoxy)-N-methylpicolinamide
18.4-((4-Chlorophenyl)(pyridin-2-yl)methoxy)piperidin-1-yl)(4-hydroxy-3
methoxyphenyl)methanone
19.4-Hydroxy-N-((3-hydroxy-5-(hydroxymethyl)-2-methylpyridin-4-yl)methyl)-3
methoxybenzamide
20.(6,7-Dihydrothieno[3,2-c]pyridin-5(4H)-yl)(2,5-dihydroxyphenyl)methanone
21.(4-((4-Chlorophenyl)(pyridin-2-yl)methoxy)piperidin-1-yl)(2,5
dihydroxyphenyl)methanone
22.N-((4-(4-Fluorobenzyl)morpholin-2-yl)methyl)-2,5-dihydroxybenzamide
23.(2,5-Dihydroxyphenyl)(4-(5-fluorobenzo[d]isoxazol-3-yl)piperidin-1
yl)methanone
24.N-(3,4-Dimethoxyphenethyl)-2,5-dihydroxybenzamide
25.2,5-Dihydroxy-N-(2-(thiophen-2-yl)ethyl)benzamide
26.2,5-Dihydroxy-N-(2-oxotetrahydrothiophen-3-yl)benzamide.
Thus, another aspect of the present invention relates to a compound that is
individually selected from the above group, or a pharmaceutically acceptable salt or isomer
thereof.
Yet another aspect of the present invention relates to a composition for the
prevention or treatment of thrombotic diseases due to platelet aggregation, comprising as an active ingredient a compound of Formula (I) or (II), or a pharmaceutically acceptable salt or isomer thereof. Thrombotic diseases as referred to herein may include, but are not limited to, for example, pulmonary embolism, thrombotic phlebitis, deep vein thrombosis, portal thrombosis, angina pectoris, arteriosclerosis, or cerebral infarction.
The pharmaceutical composition according to the present invention may be
formulated in a suitable form together with a conventionally used pharmaceutically
acceptable carrier(s). The term "pharmaceutically acceptable" refers to an ingredient that is
physiologically acceptable and that generally does not cause an allergic reaction such as
gastrointestinal disorder and dizziness, or a similar reaction, when administered to humans.
Examples of such pharmaceutically acceptable carriers include carriers such as water,
suitable oils, saline, aqueous glucose, and glycols for parenteral administration.
In addition, the composition according to the present invention may further comprise
a stabilizer and a preservative. Suitable stabilizers may include antioxidants such as sodium
bisulfite, sodium sulfite and ascorbic acid. Suitable preservatives may include
benzalkonium chloride, methyl- or propyl-paraben and chlorobutanol. In addition, the
composition according to the present invention may properly comprise suspending agents,
solubilizing agents, stabilizers, tonicity agents, preservatives, anti-adherents, surfactants,
diluents, excipients, pH-adjusting agents, pain-relieving agents for injection pain, buffering
agents, antioxidants, and the like, if needed depending on administration routes and dosage
forms. Pharmaceutically acceptable carriers and formulations suitable for the present
invention, including those exemplified above, are described in detail in the literature
[Remington's Pharmaceutical Sciences, Current Edition]. The compositions of the present
invention may be prepared in unit dosage form or may be prepared by incorporation into a
multi-dose container. In the pharmaceutical composition, the compounds of the present invention are present in an amount of 0.0001 to 10% by weight, preferably 0.001 to 1% by weight, based on the total weight of the total composition.
The administration method of the pharmaceutical composition of the present
invention can be easily selected depending on the type of formulation and can be
administered to mammals such as livestocks and humans in various routes, in the following
oral or parenteral administration forms.
Examples of formulations for oral administration include tablets, pills, hard/soft
capsules, liquids, suspensions, emulsions, syrups, granules, elixirs, troches and the like.
These formulations may contain, in addition to the active ingredient, diluents (for example,
lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, and/or glycine) and lubricants (for
example, silica, talc, stearic acid, and magnesium or calcium salt thereof, and/or polyethylene
glycol). The tablets may also contain binders such as magnesium aluminum silicate, starch
paste, gelatin, methyl cellulose, sodium carboxymethyl cellulose and/or polyvinyl pyrrolidine,
and may optionally contain disintegrants thereof such as starch, agar, alginic acid or its
sodium salt; or effervescent mixtures and/or absorbents, colorants, flavors and sweeteners.
Formulations for parenteral administration include sterile aqueous solutions, non
aqueous solutions, suspensions, emulsions, freeze-dried lyophilizedd) preparations and
suppositories. Propylene glycol, polyethylene glycol, vegetable oil such as olive oil,
injectable ester such as ethyl oleate and the like may be used for the non-aqueous solutions
and suspensions. Witepsol, macrogol, tween 61, cacao butter, sevum laurin, glycerol,
gelatin and the like may be used as a base for suppositories. In order to prepare the
formulation for parenteral administration, the compounds of Formula (I) or (II) or a
pharmaceutically acceptable salt thereof may be sterilized and/or mixed in water with additives such as preservatives, stabilizers, hydrating agents or emulsifying accelerators, salts and/or buffers for adjusting osmotic pressure, and other therapeutically useful substances to prepare solutions or suspensions, which may be prepared in ampoules or vial unit dosage forms.
Preferable doses for the human body of the pharmaceutical composition of the
present invention that comprises the compounds of Formula (I) or (II) as an active ingredient
will vary depending on the condition and weight of the patient, the degree of disease, the type
of drug, the route of administration, and the treatment duration, but can be appropriately
selected by those skilled in the art. Preferably, however, the compounds of the present
invention can be administered at a daily dose of 0.001 to 100 mg/kg body weight, more
preferably 0.01 to 30 mg/kg body weight. The administration maybe carried out once a day
or divided into several times a day. The doses may vary depending on various conditions
such as the patient's body weight, age, sex, health condition, diet, time of administration,
administration method, excretion rate and severity of disease, and thus it will be apparent to
those skilled in the art that the doses may be additive or subtractive. Therefore, the above
doses do not in any way limit the scope of the invention. The number of administrations
may be once a day or several times a day within a desired range, and the administration
period is not particularly limited.
The compounds represented by Formula (I) or (II) as described above activate
platelet aggregation inhibition.
Shear stress is a physical stimulus applied to blood cells such as platelets and red
blood cells and to vascular endothelium by blood flow. In normal conditions, it is
maintained at a low level of 300 to 1500 s-1, but it increases abnormally and even increases to
,000 s- or more when the blood vessels are narrowed for pathological reasons such as
stenosis, arteriosclerosis, cancer, and vasospasm. This excessively elevated shear stress can
directly activate and aggregate platelets, whose condition is defined as shear stress-induced
platelet aggregation (SIPA). Shear stress-induced platelet aggregation is initiated by the
binding of von Willebrand factor (vWF) with glycoprotein (GP) Ib, and is followed by
increased intracellular calcium concentration, secretion of active factors from the granule,
and expression of adherent proteins, which lead to stable platelet aggregation and
thrombogenesis.
Practically, shear stress is one of the most important causes of pathologic arterial
thrombosis in vivo, but to date no drug has been developed or is under development that
targets shear stress-induced platelet aggregation. Hence, the development of such a drug
will be a first-in-class and it is expected to pave the way for new markets as well as replacing
existing products. Particularly, unlike other chemical agonists, this drug induces platelet
activation through a novel mechanism and is advantageous in reflecting the in vivo
environment caused by changes in blood flow, and it is expected that its mechanism of action
is subdivided into 5 steps of vWF-GP Ib binding, intracellular Ca change, GP Ilb/IIla
activation, vWF secretion, and ADAMTS13 activation.
In addition, the compounds represented by Formula (I) or (II) of the present
invention show almost no side effects such as bleeding even when taken for a long time,
unlike the conventional antiplatelet agents.
As used herein, the term "prevention (preventing)" refers to any act that inhibits or
delays the onset of a related disease upon administration of the composition according to the
invention. It will be apparent to those skilled in the art that the composition of the present invention can prevent such a disease when administered before or in the early stage of the onset of symptoms.
As used herein, the term "treatment (treating)" refers to any act that improves or
changes into an advantageous state the symptoms of a related disease upon administration of
the composition according to the present invention, and it includes alleviation and
improvement. Any person having ordinary skill in the art will be able to know the precise
criteria of the disease and can judge the degree of alleviation, improvement and treatment of
the disease by referring to the data presented by the Korean Medical Association, etc.
Yet another aspect of the present invention relates to a method for treating or
preventing thrombosis comprising administering a therapeutically effective amount of the
composition according to the present invention to a subject in need of treatment of
thrombosis.
The term "subject" as used herein refers to a subject in need of treatment of a disease,
and more specifically refers to mammals including humans, non-human primates, mice, rats,
dogs, cats, horses and cows.
The method of administering the composition according to the present invention to a
subject can be carried out as described above.
The term "therapeutically effective amount" as used herein refers to an amount of the
compounds according to the present invention or the pharmaceutical composition comprising
said compounds that is sufficient to treat, inhibit, alleviate or prevent thrombosis as described
above, which may be determined by conducting a benefit/risk ratio determination that is
applied to any drug. However, the total daily dose may be determined by the physician's reasonable opinion. In addition, the daily dose of a particular patient may also be determined by considering a variety of factors known in the art, such as, for example, the type of specific disease, the severity of the disease, the type of the particular drug administered, the type of composition used, the patient's age, body weight, general health condition, sex, diet, the time of administration, the route of administration, the absorption, distribution and excretion rate of the drug, the duration of the administration, the type of other drug used, and the like. Furthermore, at the initial stage of drug administration, a drug is administered in an amount less than that required for the desired effect, and the dose is gradually increased until the desired effect is obtained.
[Effect of the Invention]
The compounds according to the present invention, or pharmaceutically acceptable
salts or isomers thereof, have an effect of inhibiting platelet aggregation, and the composition
comprising the same can efficiently prevent or treat a thrombotic disease with few side
effects such as bleeding.
[Specific embodiments of the Invention]
Hereinafter, in order to facilitate understanding of the present invention, examples
will be presented. However, the following examples are provided only for the purpose of
easier understanding of the present invention, and the present invention is not limited to the
following examples.
Examples
Preparation of Experiments and Instruments
1. Analytical instruments
The following instruments were used to identify the structure of the product obtained
in this experiment. The nuclear magnetic resonance spectrum (1 H-NMR) was used with
300 MHz or 400 MHz, and the solvents were CDCl 3 and DMSO-d6. The coupling constant
(J) was expressed in Hz. The mass spectrum (manufacturer: JEOL / model name: JMS-AX
505wA spectrometer; or manufacturer: JEOL / model name: JMS-HX / HX 1I1A
spectrometer) was used according to the manufacturer's manual and expressed in m/z form.
2. TLC and column chromatography
Silica gel (Merck F254) from Merck was used for thin layer chromatography (TLC)
and silica (Merck EM 9385, 230-400 mesh) was used for column chromatography. In
addition, to confirm the separated substances on TLC, the plate was monitored under UV
lamp (at 254 nm), or the plate was immersed in anisaldehyde and potassium permanganate
(KMnO4) color development reagents, followed by heating.
3. Reagents used
The reagents used in this experiment were purchased from Sigma-Aldrich, Lancaster,
or Fluka, and the solvents used in the reaction were purchased from Sigma-Aldrich, Merck or
Junsei Chemical Co. (Japan). The first grade reagents were used without purification. THF
used as the solvent was prepared by heating under reflux over sodium metal in the presence
of benzophenone in an argon stream until it turned blue. Dichloromethane (CH 2 Cl 2 ) was
prepared by adding CaH 2 in an argon stream and heating under reflux. Ethyl acetate and
hexane were heated under reflux in an argon stream and purified.
Preparation Example 1: Preparation of 3,4-Diacetoxybenzoic acid
10.0 g of PCA was added to a mixture of 150 mL of purified water and 36.1 mL of
TEA, and 18.4 mL of acetic anhydride was added dropwise at 20°C or lower. The mixture
was stirred at room temperature overnight. Hydrochloric acid was added thereto to adjust
the pH to 3.0, and the mixture was stirred at room temperature for 1 hour. The resulting
solid was filtered, washed with purified water, and dried at 40°C to obtain 9.2 g of the title
compound as a white solid.
Yield: 59.5%
H NMR (400MHz, CDC 3) 68.05 (dd, J= 2.0 and 8.4 Hz, 1H), 7.97 (d, J= 2.0 Hz,
1H), 7.35(d, J= 8.8 Hz, 1H), 2.35(s, 3H), 2.34 (s, 3H)
Preparation Example 2: Preparation of 4-Acetoxy-3-methoxybenzoic acid
Vanillic acid (10.0 g) was added to a mixture of 150 mL of purified water and 16.5
mL of TEA, and 8.4 mL of acetic anhydride was added dropwise at 20°C or lower. The
mixture was stirred at room temperature overnight. Hydrochloric acid was added thereto to
adjust the pH to 3.0, and the mixture was stirred at room temperature for 1 hour. The
resulting solid was filtered, washed with purified water and dried at 40°C to obtain 10.7 g of
the title compound as an ocher-colored solid.
Yield: 85.5%
1H NMR (400MHz, CDC 3) 67.78 (dd, J= 6.4 and 8.0 Hz, 1H), 7.73 (d, J= 2.0 Hz,
1H), 7.16(d, J= 8.4 Hz, 1H), 3.93(s, 3H), 2.37 (s, 3H)
Example 1: (6,7-Dihydrothieno[3,2-c]pyridin-5(4H)-y)(3,4-dihydroxyphenyl)methanone
0.5 g of 3,4-diacetoxybenzoic acid obtained in Preparation Example 1 was added to
DCM 10 mL, and the mixture was stirred at 10°C. 0.66 g of PCls was added at 10°C or
lower, the mixture was stirred for 2 hours while maintaining the temperature at 0 to 10°C, and
ml of purified water was added for extraction. The aqueous layer was discarded, and the
organic layer was dried over Na2 SO 4 and filtered. The filtrate was concentrated, 10 mL of
DCM was added, cooled to 0°C, and 0.33 g of 4,5,6,7-tetrahydrothieno[3,2,c]pyridine
hydrochloride was added. 0.44 mL of TEA was added dropwise while maintaining the
temperature at 0°C, the temperature was gradually raised to room temperature, and the
mixture was stirred for 2 hours. DCM phase was concentrated and 10 mL of EtOAC and 10
mL of purified water were added for layer separation. The aqueous layer was further
extracted with 10 mL of EtOAc, the residual aqueous layer was discarded, and the organic
layer was concentrated. 5 mL of MeOH, 5 mL of purified water and 2.9 mL of TEA were
added to the concentrate, and the mixture was refluxed for 4 hours. The MeOH phase was
concentrated, 10 mL of EtOAc and 10 mL of purified water were added, and the layers were
separated. The organic layer was concentrated, and sonicated for 5 minutes after the
addition of a small amount of DCM. The resulting solid was filtered and washed with a
small amount of DCM to obtain 0.38 g of the title compound as a white solid.
Yield: 65.7%
H NMR(400MHz,DMSO-d )69.30(brs,2H),7.35(d,J=4.0Hz,1H), 6 6.88(brs,
1H), 6.84 (s, 1H), 6.77(d, J= 4.0 Hz, 1H), 4.64(s, 1H), 3.96(s, 1H), 3.87 (s, 1H), 2.89 (s, 1H),
2.81 (s, 1H)
Example 2: (3,4-Dihydroxyphenyl)(4-(5-fluorobenzo[d]isoxazol-3-yl)piperidin-1
yl)methanone
0.5 g of 3,4-diacetoxybenzoic acid obtained in Preparation Example 1 was added to
DCM 10 mL, and the mixture was stirred at 10°C. 0.66 g of PCls was added at 10°C or
lower, the mixture was stirred for 2 hours while maintaining the temperature at 0 to 10°C, and
ml of purified water was added to extraction. . The aqueous layer was discarded and the
organic layer was dried over Na2 SO 4 and filtered. The filtrate was concentrated, 10 mL of
DCM was added, cooled to0°C, and 0.48 g of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole
hydrochloride was added. 0.44 mL of TEA was added dropwise while maintaining the
temperature at 0°C, the temperature was gradually raised to room temperature, and the
mixture was stirred for 2 hours. DCM phase was concentrated, and 10 mL of EtOAC and
mLof purified water were added for extraction. The aqueous layer was further extracted
with 10 mL of EtOAc, the residual aqueous layer was discarded, and the organic layer was
concentrated. 5 mL of MeOH, 5 mL of purified water and 2.9 mL of TEA were added to the
concentrate, and the mixture was refluxed for 4 hours. The MeOH phase was concentrated,
mL of EtOAc and 10 mL of purified water were added, and the layers were separated.
The organic layer was concentrated and sonicated for 5 mines after the addition of a small
amount of DCM. The resulting solid was filtered and washed with a small amount of DCM
to obtain 0.42 g of the title compound as a white solid.
Yield: 56.1%
H NMR (400MHz, DMSO-d) 6 9.23 (brs, 2H), 8.07(dd, J= 5.6 and 8.8 Hz, 1H),
7.71(dd, J= 2.0 and 9.2 Hz, 1H), 7.30(td, J= 2.0 and 9.2 Hz, 1H), 6.84(d, J= 1.6 Hz, 1H),
6.76~6.75(m, 2H), 4.19(brs, 2H), 3.53~3.46(m, 2H), 3.12(brs, 1H-), 2.10~2.07(m, 2H),
1.83~1.73(m, 1H)
Example 3: N-((4-(4-Fluorobenzyl)morpholin-2-yl)methyl)-3,4-dihydroxybenzamide
3.0 g of 3,4-diacetoxybenzoic acid obtained in Preparation Example 1 was added to
DCM 60 mL, and the mixture was stirred at 10°C. 3.9 g of PCl5 was added at 10°C orlower, the mixture was stirred for 2 hours while maintaining the temperature at 0 to 10°C, and 60 ml of purified water was added for layer separation. The aqueous layer was discarded and the organic layer was dried over Na 2 SO 4 and filtered. The filtrate was concentrated, added with mL of DCM, cooled to0°C, and 2.7 g of 3-aminomethy-4-(4-fluorobenzyl)morpholine was added. 5.2 mL of TEA was added dropwise while maintaining the temperature at 0°C, the temperature was gradually raised to room temperature, and the mixture was stirred for 2 hours. DCM phase was concentrated and 60 mL of EtOAC and 60 mL of purified water were added for extraction. The aqueous layer was further extracted with 60 mL of EtOAc, the aqueous residual layer was discarded, and the organic layer was concentrated. 3 mL of
MeOH, 3 mL of purified water and 17.5 mL of TEA were added to the concentrate, and the
mixture was refluxed for 4 hours. The MeOH phase was concentrated and 60 mL of EtOAc
and 60 mL of purified water were added for extraction. The organic layer was concentrated,
purified by flash column chromatography, and vacuum-dried to obtain 2.9 g of the title
compound as a foam.
Yield: 63.8% 1H NMR (400MHz, DMSO-d) 69.45 (brs, 1H), 9.11(brs, 1H), 8.18(t, J= 5.6 Hz,
1H), 7.33(dd, J= 5.6 and 8.4 Hz, 2H), 7.27(d, J= 1.6 Hz, 1H), 7.197.11(m, 3H), 6.75(d, J=
8.4 Hz, 1H), 3.77(d, J= 10.8 Hz, 1H), 3.59-3.40(m, 4H), 3.29-3.17(m, 2H), 2.73(d, J= 11.2
Hz,1H), 2.55(d,J=11.2Hz,1H),2.04(t,J=10.4Hz,1H),1.82(d,J= 10.4Hz,1H)
Example 4: 3,4-Dihydroxy-N-(2-oxotetrahydrothiophen-3-yl)benzamide
To 10 mL of DMF were added 0.5 g of protocatechuic acid, 0.68 g of EDC, 0.48 g of
HOBt, 1.4 mL of TEA and 0.55 g of homosystein thiolactone hydrochloride, and the mixture
was stirred at 60 to 80°C for 4 hours. 10 mL of EtOAc and 10 mL of purified water were
added to the reaction mixture and the layers were separated. The aqueous layer was extracted once with 10 mL of EtOAc and the aqueous layer was discarded. The organic layer was washed three times with 10 mL of purified water, dried over Na 2 SO4, and filtered.
The filtrate was concentrated by distillation under reduced pressure and purified by flash
column chromatography to obtain 0.28 g of the title compound as a white solid.
Yield: 34.1% 1H NMR(400MHz, DMSO-d) 9.52(brs, 1H), 9.17(brs, 1H), 8.42(d, J=8.0, 1H),
7.29(d, J=2.0, 1H), 7.20(dd, J=2.0 and 8.4, 1H), 6.77(d, J=8.8, 1H), 4.79(sex, J=7.6, 1H),
3.47-3.29(m, 2H), 2.46-2.22(m, 2H)
Example 5: N,N'-(Nonan-1,9-diyl)bis(3,4-dihydroxybenzamide)
0.5 g of 3,4-diacetoxybenzoic acid obtained in Preparation Example 1 was added to
DCM 10 mL, and the mixture was stirred at 10°C. 0.66 g of PCls was added at 10°C or
lower, the mixture was stirred for 2 hours while maintaining the temperature at 0 to 10°C, and
ml of purified water was added for layer separation. The aqueous layer was discarded
and the organic layer was dried over Na 2 SO 4 and filtered. The filtrate was concentrated,
added with 10 mL of DCM, cooled to0°C, and 0.13 g of 1,9-diaminononane was added.
0.44 mL of TEA was added dropwise while maintaining the temperature at 0°C, the
temperature was gradually raised to room temperature, and the mixture was stirred for 2
hours. DCM was concentrated and 10 mL of EtOAC and 10 mL of purified water were
added for layer separation. The aqueous layer was extracted with 10 mL of EtOAc, the
aqueous layer was discarded, and the organic layer was concentrated. 5 mL of MeOH, 5 mL
of purified water and 2.9 mL of TEA were added to the concentrate, and the mixture was
refluxed for 4 hours. The MeOH solution was concentrated, 10 mL of EtOAc and 10 mL of
purified water were added, and the layers were separated. The organic layer was
concentrated under reduced pressure and purified by flash column chromatography to obtain
0.65 g of the title compound as a white solid.
Yield: 71.9%
H NMR (400MHz, DMSO-d) 6 9.40 (brs, 2H), 9.08(brs, 2H), 8.10(t, J= 5.6 Hz,
2H), 7.26(d, J= 2.4 Hz, 2H), 7.17(dd, J= 2.0 and 8.0 Hz, 2H), 6.74(d, J= 8.0 Hz, 2H),
3.09(q, J= 6.8 Hz, 4H), 1.47(t, J= 6.0 Hz, 4H), 1.27(s, I1H)
Example 6: (4-((4-Chlorophenyl)(pyridin-2-yl)methoxy)piperidin-1-y)(3,4
dihydroxyphenyl)methanone
0.5 g of 3,4-diacetoxybenzoic acid obtained in Preparation Example 1 was added to
DCM 10 mL, and the mixture was stirred at 10°C. 0.66 g of PCls was added at 10°C or
lower, the mixture was stirred for 2 hours while maintaining the temperature at 0 to 10°C, and
ml of purified water was added for layer separation. The aqueous layer was discarded
and the organic layer was dried over Na 2 SO 4 and filtered. The filtrate was concentrated,
added with 10 mL of DCM, cooled to 0°C, and 0.57 g of 2-[(4-chlorophenyl)(4
piperidinyloxy)methyl]pyridine was added. 0.44 mL of TEA was added dropwise while
maintaining the temperature at 0°C, the temperature was gradually raised to room
temperature, and the mixture was stirred for 2 hours. DCM phase was concentrated and 10
mL of EtOAC and 10 mL of purified water were added for layer separation. The aqueous
layer was further extracted with 10 mL of EtOAc, the residual aqueous layer was discarded,
and the organic layer was concentrated. 5 mL of MeOH, 5 mL of purified water and 2.9 mL
of TEA were added to the concentrate, and the mixture was refluxed for 4 hours. The
MeOH phase was concentrated, 10 mL of EtOAc and 10 mL of purified water were added,
and the layers were separated. The organic layer was concentrated under reduced pressure
and purified by flash column chromatography to obtain 0.72 g of the title compound as a
foam.
Yield: 78.1%
H NMR (400MHz, DMSO-d) 69.25 (brs, 2H), 8.47 (d, J= 4.8 Hz, 1H), 7.81 (td, J
= 1.6 and 7.6 Hz, 1H), 7.57(d, J= 8.0 Hz, H), 7.44-7.24(m, 5H), 6.806.67(m, 3H), 5.70(s,
1H), 3.76(brs, 1H), 3.66(brs, 2H), 3.19(brs, 2H), 1.85(brs, 2H), 1.53(brs, 2H)
Example 7: (S)-(4-((4-Chlorophenyl)(pyridin-2-yl)methoxy)piperidin-1-y)(3,4
dihydroxyphenyl)methanone
0.5 g of 3,4-diacetoxybenzoic acid obtained in Preparation Example 1 was added to
DCM 10 mL, and the mixture was stirred at 10°C. 0.66 g of PCls was added at 10°C or
lower, the mixture was stirred for 2 hours while maintaining the temperature at 0 to 10°C, and
ml of purified water was added for layer separation. The aqueous layer was discarded
and the organic layer was dried over Na 2 SO 4 and filtered. The filtrate was concentrated, 10
mL of DCM was added, cooled to 0°C, and 0.57 g of (s)-2-[(4-chlorophenyl)(4
piperidinyloxy)methyl]pyridine was added. 0.44 mL of TEA was added dropwise while
maintaining the temperature at 0°C, the temperature was gradually raised to room
temperature, and the mixture was stirred for 2 hours. DCM phase was concentrated and 10
mL of EtOAC and 10 mL of purified water were added for layer separation. The aqueous
layer was further extracted with 10 mL of EtOAc, the residual aqueous layer was discarded,
and the organic layer was concentrated. 5 mL of MeOH, 5 mL of purified water and 2.9 mL
of TEA were added to the concentrate, and the mixture was refluxed for 4 hours. The
MeOH phase was concentrated, 10 mL of EtOAc and 10 mL of purified water were added,
and the layers were separated. The organic layer was concentrated under reduced pressure
and purified by flash column chromatography to obtain 0.47 g of the title compound as a
foam.
Yield: 51.0%
H NMR (400MHz, CDCl3 ) 6 8.50 (brs, 2H), 7.72 (t, J= 6.8 Hz, 1H), 7.52 (d, J= 7.6
Hz, 1H), 7.38-7.21(m, 5H), 6.84(s, 1H), 6.72(s, 2H), 5.65(s, 1H), 3.91(brs, 1H), 3.69(brs,
2H), 3.40(brs, 1H), 3.31(brs, 1H), 1.73(brs, 4H)
Example 8: (S)-Methyl-2-(3,4-dihydroxybenzamido)-3-(1H-indol-3-yl)propanoate
To 10 mL of DMF were added 0.5 g (3.24 mmol) of protocatechuic acid, 0.68 g (3.57
mmol) of EDC, 0.48 g (3.57 mmol) of HOBt and 1.58 mL (11.35 mmol) of TEA and 1.0 g
(3.89 mmol) of D-tryptophan methylester hydrochloride, and the mixture was stirred at 60 to
°Cfor4hours. 10 mL of EtOAc and 10 mL of purified water were added to the reaction
mixture and the layers were separated. The aqueous layer was extracted once with 10 mL of
EtOAc and the aqueous layer was discarded. The organic layer was washed three times
with 10 mL of purified water, dried over Na 2 SO 4 and filtered. The filtrate was concentrated
with distillation under reduced pressure and purified by flash column chromatography to
obtain 0.37 g of the title compound as a foam.
Yield: 33.6% 1H NMR (400MHz, DMSO-d) 6 10.84 (s, 1H), 9.51(s, 1H), 9.14(s, 1H), 8.42(d, J
7.2 Hz, 1H), 7.54(d, J = 7.6 Hz, 1H), 7.33(d, J = 8.0 Hz, 1H), 7.26(d, J = 2.0 Hz, 1H),
7.21-7.19(m, 2H), 7.086.97(m, 2H), 6.75(d, J= 8.0 Hz, 1H), 4.63(td, J= 5.6 and 7.6 Hz,
1H-), 3.61(s, 3H), 3.27~3.21(m, 2H)
Example 9: 4-(3,4-Dihydroxybenzamido)-1-methyl-3-propyl-1H-pyrazole-5
carboxamide
0.5 g of 3,4-diacetoxybenzoic acid obtained in Preparation Example 1 was added to
DCM 10 mL, and the mixture was stirred at 10°C. 0.66 g of PCls was added at 10°C or
lower, the mixture was stirred for 2 hours while maintaining the temperature at 0 to 10°C, and ml of purified water was added for layer separation. The aqueous layer was discarded and the organic layer was dried over Na 2 SO 4 and filtered. The filtrate was concentrated, added with 10 mL of DCM, cooled to0°C, and 0.41 g of 4-amino--methyl-3-propyl-1H pyrazole-5-carboxamide hydrochloride was added. 0.44 mL of TEA was added dropwise while maintaining the temperature at 0°C, the temperature was gradually raised to room temperature, and the mixture was stirred for 2 hours. DCM phase was concentrated and 10 mL of EtOAC and 10 mL of purified water were added for layer separation. The aqueous layer was further extracted with 10 mL of EtOAc, the aqueous layer was discarded, and the organic layer was concentrated. 5 mL of MeOH, 5 mL of purified water and 2.9 mL of TEA were added to the concentrate, and the mixture was refluxed for 4 hours. The MeOH phase was concentrated, 10 mL of EtOAc and 10 mL of purified water were added, and the layers were separated. The organic layer was concentrated by distillation under reduced pressure to give a residue in the form of foam. The residue was crystallized in a mixed solvent of
EtOAC/DCM to obtain 0.21 g of the title compound as an off-white solid.
Yield: 31.4%
H NMR (400MHz, CDC 3 ) 6 9.83(s, 1H), 9.69(brs, 1H), 9.29(brs, 1H), 7.38 (d, J=
2.0 Hz, 1H), 7.34(dd, J = 2.0 and 8.0 Hz, 1H), 6.84(d, J = 8.4 Hz, 1H), 3.94(s, 3H),
1.56(sextet, J= 7.2 Hz, 2H), 1.17(t, J= 7.2 Hz, 2H), 0.85(t, J= 7.2 Hz, 3H)
Example 10: 2-Methyl-4-oxo-4H-pyran-3-yl 3,4-dihydroxybenzoate
0.5 g of 3,4-diacetoxybenzoic acid obtained in Preparation Example 1 was added to
DCM 10 mL, and the mixture was stirred at 10°C. 0.66 g of PCls was added at 10°C or
lower, the mixture was stirred for 2 hours while maintaining the temperature at 0 to 10°C, and
ml of purified water was added for layer separation. The aqueous layer was discarded
and the organic layer was dried over Na2 SO4 , and filtered. The filtrate was concentrated, added with 10 mL of DCM, cooled to 0°C, and 0.24 g of maltol was added. 0.44 mL of
TEA was added dropwise while maintaining the temperature at 0°C, the temperature was
gradually raised to room temperature, and the mixture was stirred for 2 hours. DCM phase
was concentrated and 10 mL of EtOAC and 10 mL of purified water were added for layer
separation. The aqueous layer was further extracted with 10 mL of EtOAc, the aqueous
layer was discarded, and the organic layer was concentrated. 5 mL of MeOH, 5 mL of
purified water and 2.9 mL of TEA were added to the concentrate, and the mixture was
refluxed for 4 hours. The MeOH phase was concentrated, 10 mL of EtOAc and 10 mL of
purified water were added, and the layers were separated. The organic layer was
concentrated and sonicated for 5 minutes after addition of a small amount of DCM. The
resulting solid was filtered and washed with a small amount of DCM to obtain 0.40 g of the
title compound as a white solid.
Yield: 72.6%
H NMR (400MHz, CDC 3 ) 6 9.79(brs, 2H), 8.19 (d, J= 5.6 Hz, 1H), 7.47-7.44(m,
2H), 6.89(d, J= 8.8 Hz, 1H), 6.46(d, J= 6.0 Hz, 1H), 2.26(s, 3H)
Example 11: (3,4-Dihydroxyphenyl)(4-phenylpiperazin-1-yl)methanone
0.5 g of 3,4-diacetoxybenzoic acid obtained in Preparation Example 1 was added to
DCM 10 mL, and the mixture was stirred at 10°C. 0.66 g of PCls was added at 10°C or
lower, the mixture was stirred for 2 hours while maintaining the temperature at 0 to 10°C, and
ml of purified water was added for layer separation. The aqueous layer was discarded
and the organic layer was dried over Na 2 SO 4 and filtered. The filtrate was concentrated,
added with 10 mL of DCM, cooled to0°C, and 0.31 g of -phenylpiperazine was added.
0.44 mL of TEA was added dropwise while maintaining the temperature at 0°C, the
temperature was gradually raised to room temperature, and the mixture was stirred for 2 hours. DCM phase was concentrated and 10 mL of EtOAC and 10 mL of purified water were added, followed by layer separation. The aqueous layer was further extracted with 10 mL of EtOAc, the aqueous layer was discarded, and the organic layer was concentrated. 5 mL of MeOH, 5 mL of purified water and 2.9 mL of TEA were added to the concentrate, and the mixture was refluxed for 4 hours. The MeOH phase was concentrated, 10 mL of EtOAc and 10 mL of purified water were added, and the layers were separated. The organic layer was concentrated by distillation under reduced pressure and purified by flash column chromatography to obtain 0.28 g of the title compound as a white solid.
Yield: 45.2%
H NMR (400MHz, CDCl 3 ) 6 9.35(s, 1H), 9.21(s, 1H), 7.24-7.21(m, 2H),
6.96-6.75(m, 6H), 3.62(brs, 4H), 3.14(brs, 4H)
Example 12: (6,7-Dihydrothieno[3,2-c]pyridin-5(4H)-yl)(4-hydroxy-3
methoxyphenyl)methanone
0.5 g of 4-acetoxy-3-methoxybenzoic acid obtained in Preparation Example 2 was
added to DCM 10 mL, and the mixture was stirred at 10°C. 0.74 g of PCls was added at
°C or lower, the mixture was stirred for 2 hours while maintaining the temperature at 0 to
°C, and 10 ml of purified water was added for layer separation. The aqueous layer was
discarded and the organic layer was dried over Na2 SO 4 and filtered. The filtrate was
concentrated, added with 10 mL of DCM, cooled to 0°C, and 0.4 g of 4,5,6,7
tetrahydrothieno[3,2,c]pyridine hydrochloride was added. 0.5 mL of TEA was added
dropwise while maintaining the temperature at 0°C, the temperature was gradually raised to
room temperature, and the mixture was stirred for 2 hours. DCM phase was concentrated
and 10 mL of EtOAC and 10 mL of purified water were added for layer separation. The
aqueous layer was further extracted with 10 mL of EtOAc, the aqueous layer was discarded, and the organic layer was concentrated. 5 mL of MeOH, 5 mL of purified water and 3.3 mL of TEA were added to the concentrate, and the mixture was refluxed for 4 hours. The
MeOH phase was concentrated, and the resulting solid was filtered and washed with purified
water to obtain 0.55 g of the title compound as a white solid.
Yield: 79.9%
H NMR (400MHz, DMSO-d) 9.48 (s, 1H), 7.35 (d, J= 4.4 Hz, 1H), 7.01 (d, J
1.6 Hz, 1H), 6.93-6.90(m, 2H), 6.83 (d, J = 8.0 Hz, 1H), 4.60(s, 1H), 3.79(s, 3H),
3.74(brs, 2H), 2.88 (t, J= 4.8 Hz, 2H)
Example 13: 2-Ethyl-4-oxo-4H-pyran-3-yl 4-hydroxy-3-methoxybenzoate
0.5 g of 4-acetoxy-3-methoxybenzoic acid obtained in Preparation Example 2 was
added to DCM 10 mL, and the mixture was stirred at 10°C. 0.74 g of PCls was added at
°C or lower, the mixture was stirred for 2 hours while maintaining the temperature at 0 to
°C, and 10 ml of purified water was added thereto, followed by layer separation. The
aqueous layer was discarded and the organic layer was dried over Na 2 SO 4 and filtered. The
filtrate was concentrated, 10 mL of DCM was added, cooled to 0°C, and 0.31 g of ethylmaltol
was added. 0.5 mL of TEA was added dropwise while maintaining the temperature at0°C,
the temperature was gradually raised to room temperature, and the mixture was stirred for 2
hours. DCM was concentrated and 10 mL of EtOAC and 10 mL of purified water were
added, followed by layer separation. The aqueous layer was extracted with 10 mL of EtOAc,
the aqueous layer was discarded, and the organic layer was concentrated. 5 mL of MeOH, 5
mL of purified water and 3.3 mL of TEA were added to the concentrate, and the mixture was
refluxed for 4 hours. The MeOH was concentrated, 10 mL of EtOAc and 10 mL of purified
water were added, and the layers were separated. The organic layer was distilled under
reduced pressure and purified by flash column chromatography to obtain 0.34 g of the title compound as a white solid.
Yield: 49.2%
H NMR (400MHz, DMSO-d )6 10.24 (s, H), 8.23 (d, J= 5.2 Hz, 1H), 7.63 (d, J
7.6 Hz, 1H), 7.53(s, 1H), 6.95 (d, J= 8.0 Hz, 1H), 6.48 (d, J= 5.6 Hz, 1H), 3.85(s, 3H), 2.62
(q, J= 6.8 Hz, 2H), 1.15 (t, J= 7.2 Hz, 3H)
Example 14: 2-Methyl-4-oxo-4H-pyran-3-yl 4-hydroxy-3-methoxybenzoate
0.5 g of 4-acetoxy-3-methoxybenzoic acid obtained in Preparation Example 2 was
added to DCM 10 mL, and the mixture was stirred at 10°C. 0.74 g of PCls was added at
°C or lower, the mixture was stirred for 2 hours while maintaining the temperature at 0 to
°C, and 10 ml of purified water was added thereto, followed by layer separation. The
aqueous layer was discarded and the organic layer was dried over Na 2 SO 4 and filtered. The
filtrate was concentrated, 10 mL of DCM was added, cooled to 0°C, and 0.27 g of maltol was
added. 0.5 mL of TEA was added dropwise while maintaining the temperature at 0°C, the
temperature was gradually raised to room temperature, and the mixture was stirred for 2
hours. DCM was concentrated and 10 mL of EtOAC and 10 mL of purified water were
added, followed by layer separation. The aqueous layer was extracted with 10 mL of EtOAc,
the aqueous layer was discarded, and the organic layer was concentrated. 5 mL of MeOH, 5
mL of purified water and 3.3 mL of TEA were added to the concentrate, and the mixture was
refluxed for 4 hours. The MeOH was concentrated, and the resulting solid was filtered and
washed with purified water to obtain 0.35 g of the title compound as a white solid.
Yield: 53.2%
H NMR (400MHz, DMSO-d) 10.24 (s, 1H), 8.21 (d, J= 5.6 Hz, 1H), 7.63 (d, J
8.4 Hz, 1H), 7.53(s, 1H), 6.95 (d, J= 8.0 Hz, 1H), 6.48 (d, J= 5.6 Hz, 1H), 3.85(s, 3H),
2.83(s, 3H)
Example 15: 4-Hydroxy-3-methoxy-N-(4-methoxy-2-nitrophenyl)benzamide
0.5 g of 4-acetoxy-3-methoxybenzoic acid obtained in Preparation Example 2 was
added to DCM 10 mL, and the mixture was stirred at 10°C. 0.74 g of PCls was added at
°C or lower, the mixture was stirred for 2 hours while maintaining the temperature at 0 to
°C, and 10 ml of purified water was added thereto, followed by layer separation. The
aqueous layer was discarded and the organic layer was dried over Na 2 SO 4 and filtered. The
filtrate was concentrated, 10 mL of DCM was added, cooled to 0C, and 0.40 g of 4
methoxy-2-nitroaniline was added. 0.5 mL of TEA was added dropwise while maintaining
the temperature at 0°C, the temperature was gradually raised to room temperature, and the
mixture was stirred for 2 hours. DCMwas concentrated and 10 mL of EtOAC and 10 mLof
purified water were added, followed by layer separation. The aqueous layer was extracted
with 10 mL of EtOAc, the aqueous layer was discarded, and the organic layer was
concentrated. 5 mL of MeOH, 5 mL of purified water and 3.3 mL of TEA were added to the
concentrate, and the mixture was refluxed for 4 hours. The MeOH was concentrated, 10 mL
of EtOAc and 10 mL of purified water were added, and the layers were separated. The
organic layer was distilled under reduced pressure and purified by flash column
chromatography to obtain 0.54 g of the title compound as a red solid.
Yield: 71.3% 1H NMR(400MHz, DMSO-d) 10.32(s, 1H), 9.81(brs, 1H)7.63(d, J=8.8, 1H),
7.52-7.46(m, 3H), 7.35(dd, J=2.8 and 8.8, 1H), 3.86(s, 1H), 3.85(s, 3H)
Example 16: N-(3-Ethynylphenyl)-4-hydroxy-3-methoxybenzamide
0.5 g of 4-acetoxy-3-methoxybenzoic acid obtained in Preparation Example 2 was
added to DCM 10 mL, and the mixture was stirred at 10°C. 0.74 g of PCls was added at
°C or lower, the mixture was stirred for 2 hours while maintaining the temperature at 0 to
°C, and 10 ml of purified water was added thereto, followed by layer separation. The
aqueous layer was discarded and the organic layer was dried over Na 2 SO 4 and filtered. The
filtrate was concentrated, 10 mL of DCM was added, cooled to 0C, and 0.25 g of 3
aminophenylacetylene was added. 0.5 mL of TEA was added dropwise while maintaining
the temperature at 0°C, the temperature was gradually raised to room temperature, and the
mixture was stirred for 2 hours. DCMwas concentrated and 10 mL of EtOAC and 10 mLof
purified water were added, followed by layer separation. The aqueous layer was extracted
with 10 mL of EtOAc, the aqueous layer was discarded, and the organic layer was
concentrated. 5 mL of MeOH, 5 mL of purified water and 3.3 mL of TEA were added to the
concentrate, and the mixture was refluxed for 4 hours. The MeOH was concentrated, 10 mL
of EtOAc and 10 mL of purified water were added, and the layers were separated. The
organic layer was distilled under reduced pressure. To the resulting solid was added a small
amount of IPA and stirred to obtain 0.30 g of the title compound as a white solid.
Yield: 47.2%
H NMR (400MHz, DMSO-d) 6 10.07 (s, 1H), 9.75(brs, 1H), 7.92 (d, J= 1.2 Hz,
1H), 7.80 (dd, J= 1.2 and 8.4 Hz, 1H), 7.54-7.50(m, 2H), 7.36 (t, J= 8.0 Hz, 1H), 7.10 (dd,
J= 1.2 and 8.0 Hz, 1H), 6.90 (d, J= 8.0 Hz, 1H), 4.18(s, 1H), 3.87(s, 3H)
Example 17: 4-(4-(4-Hydroxy-3-methoxybenzamido)phenoxy)-N-methylpicolinamide
0.5 g of 4-acetoxy-3-methoxybenzoic acid obtained in Preparation Example 2 was
added to DCM 10 mL, and the mixture was stirred at 10°C. 0.74 g of PCls was added at
°C or lower, the mixture was stirred for 2 hours while maintaining the temperature at 0 to
°C, and 10 ml of purified water was added thereto, followed by layer separation. The
aqueous layer was discarded and the organic layer was dried over Na 2 SO 4 and filtered. The filtrate was concentrated, 10 mL of DCM was added, cooled to 0°C, and 0.55 g of 4-(4 aminophenoxy)-N-methylpicolinamide was added. 0.5 mL of TEA was added dropwise while maintaining the temperature at 0°C, the temperature was gradually raised to room temperature, and the mixture was stirred for 2 hours. DCM was concentrated and 10 mL of
EtOAC and 10 mL of purified water were added, followed by layer separation. Theaqueous
layer was extracted with 10 mL of EtOAc, the aqueous layer was discarded, and the organic
layer was concentrated. 5 mL of MeOH, 5 mL of purified water and 3.3 mL of TEA were
added to the concentrate, and the mixture was refluxed for 4 hours. The MeOH was
concentrated, 10 mL of EtOAc and 10 mL of purified water were added, and the layers were
separated. The organic layer was distilled under reduced pressure and purified by flash
column chromatography to obtain 0.48 g of the title compound as a light yellow solid.
Yield: 51.3% 1H NMR(400MHz, CDC 3 ) 8.60(s, 1H), 8.39(d, J=5.6, 1H), 8.10(q, J=5.2, 1H),
7.71-7.65(m, 3H), 7.52(d, J=2.0, 1H), 7.43(dd, J=2.0 and 8.4, 1H), 7.046.90(m, 4H),
6.73(brs, 1H), 3.78(s, 3H), 3.01(d, J=5.2, 3H)
Example 18: 4-((4-Chlorophenyl)(pyridin-2-yl)methoxy)piperidin-1-y)(4-hydroxy-3
methoxyphenyl)methanone
To 10 mL of DMF were added 0.5 g of vanillic acid, 0.51 g of EDC, 0.44 g of HOBt,
1.44 mL of TEA and 0.99 g of 2-[(4-chlorophenyl)(4-piperidinyloxy)methyl]pyridine, and the
mixture was stirred at 60 to 80°C for 4 hours. 10 mLofEtOAc and 10 mLofpurifiedwater
were added to the reaction mixture and the layers were separated. The aqueous layer was
extracted once with 10 mL of EtOAc and the aqueous layer was discarded. The organic
layer was washed three times with 10 mL of purified water, dried over Na 2 SO 4 and filtered.
The filtrate was distilled under reduced pressure and purified by flash column chromatography to obtain 0.40 g of the title compound as a pale yellow solid.
Yield: 31.6%
H NMR (400MHz, DMSO-d6) 6 9.41 (brs, H), 8.47 (d, J= 4.0 Hz, 1H), 7.81 (t, J
7.0,1H),7.57(d,J=8.0Hz,H),7.446.94(m,6H),6.846.67(m,3H),5.71(s,1H), 3.87(s,
3H), 3.74-3.69(m, 2H), 3.37(brs, 2H), 1.85(brs, 2H), 1.72(brs, 2H)
Example 19: 4-Hydroxy-N-((3-hydroxy-5-(hydroxymethylmethyl)-2-methylpyridin-4
yl)methyl)-3-methoxybenzamide
To 10 mL of DMF were added 0.5 g of vanillic acid, 0.51 g of EDC, 0.44 g of HOBt,
1.44 mL of TEA and 0.72 g of pyridoxoamine 2HCl, and the mixture was stirred at 60 to
°Cfor4hours. 10 mL of EtOAc and 10 mL of purified water were added to the reaction
mixture and the layers were separated. The aqueous layer was extracted once with 10 mL of
EtOAc and the aqueous layer was discarded. The organic layer was washed three times
with 10 mL of purified water, dried over Na 2 SO 4 and filtered. The filtrate was distilled
under reduced pressure and purified by flash column chromatography to obtain 0.62 g of the
title compound as a pale yellow solid.
Yield: 65.6% 1H NMR(400MHz, DMSO-d) 10.50(s, 1H), 9.76(s, 1H), 9.18(t, J=5.6, 1H), 7.29(s,
1H), 7.47(d, J=2.0, 1H), 7.42(dd, J=2.0 and 8.4, 1H), 6.83(d, J=8.4, 1H), 5.25(t, J=5.2, 1H),
4.67(d, J=4.8, 2H), 4.48(d, J=6.0, 2H), 3.82(s, 3H), 2.35(s, 3H)
Example 20: (6,7-Dihydrothieno[3,2-c]pyridin-5(4H)-y)(2,5
dihydroxyphenyl)methanone
To 10 mL of DMF were added 0.5 g of gentisic acid, 0.93 g of EDC, 0.66 g of HOBt,
1.35 mL of TEA and 0.62 g of 4,5,6,7-tetrahydrothieno[3,2,c] pyridine hydrochloride, and the mixture was stirred at 60 to 80°C for 4 hours. 10 mLofEtOAc and 10 mLofpurifiedwater were added to the reaction mixture and stirred. The resulting solid was filtered, refluxed in mL of EtOAc for 1 h and then filtered. The filtrate was washed with a small amount of
EtOAc to obtain 0.38 g of the title compound as an apricot-colored solid.
Yield: 42.6%
H NMR (400MHz, DMSO-d) 69.08 (s, 1H), 8.93 (s, 1H), 7.34 (brs, 1H), 7.35 (d, J
=4.4 Hz, 1H), 7.01 (d, J= 1.6 Hz, 1H), 6.93-6.90(m, 2H), 6.83 (d, J= 8.0 Hz, 1H), 4.60(s,
1H),3.79(s,3H), 3.74(brs,2H),2.86(t,J=4.8Hz,1H)
Example 21: (4-((4-Chlorophenyl)(pyridin-2-yl)methoxy)piperidin-1-y)(2,5
dihydroxyphenyl)methanone
To 10 mL of DMF were added 0.5 g of gentisic acid, 0.68 g of EDC, 0.48 g of HOBt,
1.4 mL of TEA and 1.08 g of 2-[(4-chlorophenyl)(4-piperidinyloxy)methyl]pyridine, and the
mixture was stirred at 60 to 80°C for 4 hours. 10 mLofEtOAc and 10 mLofpurifiedwater
were added to the reaction mixture and the layers were separated. The aqueous layer was
extracted once with 10 mL of EtOAc and the aqueous layer was discarded. The organic
layer was washed three times with 10 mL of purified water, dried over Na 2 SO 4 and filtered.
The filtrate was distilled under reduced pressure and purified by flash column
chromatography to obtain 0.78 g of the title compound as a foam.
Yield: 54.9% 1H NMR(400MHz, DMSO-d) 9.05(s, 1H), 8.89(s, 1H), 8.47(dd, J=0.8 and 4.0, 1H),
7.81(td, J=1.6 and 8.0, 1H), 7.57(d, J=7.6, 1H), 7.43-7.25(m, 5H), 6.67-6.60(m, 2H), 6.46(d,
J=2.8, 1H), 5.69(s, 1H), 3.93(brs, 1H), 3.64(p, J=4.4, 1H), 3.14(brs, 2H), 1.85(brs, 1H),
1.55~1.52(m, 2H)
Example 22: N-((4-(4-Fluorobenzyl)morpholin-2-yl)methyl)-2,5-dihydroxybenzamide
To 10 mL of DMF were added 0.5 g of gentisic acid, 0.68 g of EDC, 0.48 g of HOBt,
1.4 mL of TEA and 0.73 g of 3-aminomethyl-4-(4-fluorobenzyl)morpholine, and the mixture
was stirred at 60 to 80°C for 4 hours. 10 mL of EtOAc and 10 mL of purified water were
added to the reaction mixture and the layers were separated. The aqueous layer was
extracted once with 10 mL of EtOAc and the aqueous layer was discarded. The organic
layer was washed three times with 10 mL of purified water, dried over Na 2 SO 4 and filtered.
The filtrate was distilled under reduced pressure and purified by flash column
chromatography to obtain 0.80 g of the title compound as a foam.
Yield: 68.5% 1H NMR(400MHz, CDC 3) 7.31-7.27(m, 2H), 7.057.00(m, 4H), 6.89-6.88(m, 2H),
3.96~3.67(m, 4H), 3.49~3.33(m, 3H), 2.79(d, J=11.6, 1H-), 2.69(d, J=11.6, 1H-), 2.24~1.91(m,
2H)
Example 23: (2,5-Dihydroxyphenyl)(4-(5-fluorobenzo[d]isoxazol-3-yl)piperidin-1
yl)methanone
To 10 mL of DMF were added 0.5 g of gentisic acid, 0.68 g of EDC, 0.48 g of HOBt,
1.4 mL of TEA and 0.83 g of 6-fluoro-3-(4-piperidinyl)-1,2-benzoisoxazole hydrochloride,
and the mixture was stirred at 60 to 80°C for 4 hours. 10 mL of EtOAc and 10 mL of
purified water were added to the reaction mixture and the layers were separated. The
aqueous layer was extracted once with 10 mL of EtOAc and the aqueous layer was discarded.
The organic layer was washed three times with 10 mL of purified water, dried over Na2 SO 4
and filtered. The filtrate was distilled under reduced pressure and purified by flash column
chromatography to obtain 0.64 g of the title compound as a white solid.
Yield: 55.4%
IH NMR(400MHz, DMSO-d) 9.07(s, 1H), 8.92(s, 1H), 8.02(dd, J=5.6 and 8.8, 1H),
7.70(dd, J=1.6 and 8.8, 1H), 6.70-6.54(m, 3H), 4.57(brs, 1H), 3.61-3.45(m, 3H), 3.09(brs,
2H), 2.06(brs, 2H), 1.80(brs, 2H)
Example 24: N-(3,4-Dimethoxyphenethyl)-2,5-dihydroxybenzamide
To 10 mL of DMF were added 0.5 g of gentisic acid, 0.68 g of EDC, 0.48 g of HOBt,
1.4 mL of TEA and 0.6 mL of 3,4-dimethoxyphenethylamine, and the mixture was stirred at
to 80°C for 4 hours. 10 mL of EtOAc and 10 mL of purified water were added to the
reaction mixture and the layers were separated. The aqueous layer was extracted once with
mL of EtOAc and the aqueous layer was discarded. The organic layer was washed three
times with 10 mL of purified water, dried over Na2 SO 4 and filtered. The filtrate was
distilled under reduced pressure and purified by flash column chromatography to obtain 0.73
g of the title compound as a white solid.
Yield: 71.0%
1H NMR(400MHz, DMSO-d) 11.63(brs, 1H), 9.00(brs, 1H), 8.72(t, J=5.2, 1H),
7.22(d, J=2.8, 1H), 6.88-6.71(m, 5H), 3.72(s, 3H), 3.71(s, 3H), 3.50(q, J=6.8, 2H), 2.78(t,
J=7.6, 2H)
Example 25: 2,5-Dihydroxy-N-(2-(thiophen-2-yl)ethyl)benzamide
To 10 mL of DMF were added 0.5 g of gentisic acid, 0.68 g of EDC, 0.48 g of HOBt,
1.4 mL of TEA and 0.4 mL of thiophene-2-ethylamine, and the mixture was stirred at 60 to
°Cfor4hours. 10 mL of EtOAc and 10 mL of purified water were added to the reaction
mixture and the layers were separated. The aqueous layer was extracted once with 10 mL of
EtOAc and the aqueous layer was discarded. The organic layer was washed three times
with 10 mL of purified water, dried over Na 2 SO 4 and filtered. The filtrate was distilled under reduced pressure and purified by flash column chromatography to obtain 0.56 g of the title compound as a white solid.
Yield: 65.6% 1H NMR(400MHz, DMSO-d) 11.62(brs, 1H), 9.03(brs, 1H), 8.83(t, J=5.2, 1H),
7.34(dd, J=1.2 and 4.8, 1H), 7.23(d, J=3.2, 1H), 6.97-6.85(m, 3H), 6.73(d, J=8.8, 1H), 3.53(q,
J=6.8, 2H), 3.08(t, J=6.8, 2H)
Example 26: 2,5-Dihydroxy-N-(2-oxotetrahydrothiophen-3-yl)benzamide
To 10 mL of DMF were added 0.5 g of gentisic acid, 0.68 g of EDC, 0.48 g of HOBt,
1.4 mL of TEA and 0.55 g of homosystein thiolactone hydrochloride, and the mixture was
stirred at 60 to 80°C for4 hours. 10 mL of EtOAc and 10 mL of purified water were added
to the reaction mixture and the layers were separated. The aqueous layer was extracted once
with 10 mL of EtOAc and the aqueous layer was discarded. The organic layer was washed
three times with 10 mL of purified water, dried over Na2 SO4 and filtered. The filtrate was
distilled under reduced pressure and purified by flash column chromatography to obtain 0.21
g of the title compound as a white solid.
Yield: 25.6%
1H NMR(400MHz, DMSO-d) 11.33(brs, 1H), 9.06(brs, 1H), 8.92(d, J=8.0, 1H),
7.24(d, J=3.2, 1H), 6.89(dd, J=2.8 and 8.8, 1H), 6.77(d, J=8.8, 1H), 4.84(sex, J=5.6, 1H),
3.50-3.25(m, 2H), 2.56-2.26(m, 2H)
[Table 1]
Inhibitory effect of Example Compound shear stress-induced platelet aggregation
1~ ~ N 2-0
HO"j C S OH 0F NF 2 ~- N20-~30% HO" OH N- 0 0
~ H 3 HO N 3000or more OH ( F
0 N S
4HO" 3 0%or more OH 0 0
5 HO H H XOH 20-30%o OH OH
6 0,N LN20-~30%~ HO 0 OH )% I
1
N 7 HL20-30%o O~i:-j
HO 0'" OH ~ c /
0 0
8 H 20~300 HO"];f\ NH OH
NH 2 0 0 N 9- N -N 20-30%o IH HO** OH 00
0~ 20-~3O0% HO(C OH 0
11 N) 3 0 %or more HO OH
0
12 N N I 20-~30%o HO" S
00 0
13 0~ 20-30%o HO(
00 0 0
14 030% or more HOCC
00
IHN O 20-~30%0 o 16 IHN K-3000or more HOJP
0 O 0 N 17 N 'CN H20-30%
HO"]I:
0 oN 18 H a0 Nz30% or more
HO 0 H
'. N 19 HI N2-0 HW2~30 01 1 OH
0 HOIC H~ "' 30% or more
~OH S
0 1 HO, N N 21 O~ N20-~30%0 ~OH 0
-C 0 HO - N IH) 22 OI)OH N 30% or more
,-a F
0 F 23 HO N -20-30%
OH N- 0
0 ~ 011
24 0,H ~OH
0 S\
25 HOI: N 2 0~30% H XOH
0
26 HOI OHN -' S20-30% OH
Experimental Example
Experimental Example 1: Measurement of inhibitory effect of shear stress-induced
platelet aggregation
1-1. Measurement of platelet aggregation inhibitory effect using human platelet rich
plasma (PRP)
Blood was collected from the veins of healthy male volunteers who had not taken
any medication for more than 2 weeks. All related studies were conducted under the
approval of the Seoul National University Institutional Review Board (IRB No. 1305/001
016). During the whole process of study the use of glass containers or glass pipettes was
avoided, and the experiments were performed at room temperature. To separate platelet rich
plasma (PRP), the blood was collected with 3.2% sodium citrate as an anticoagulant. The
whole blood was centrifuged at 150 g for 15 minutes to obtain the supernatant (PRP), and the
residue was centrifuged at 2,000 g for 20 minutes to obtain platelet poor plasma (PPP). The number of platelets of the PRP thus obtained was counted with an optical microscope using a hemacytometer. PRP was diluted with PPP so as to include 3 x 108 platelets per 1 ml, and then used in the experiments. PRP was put on a cone-plate viscometer (RotoVisco 1,
Thermo Fischer Scientific, USA), and shear stress was applied to the PRP at 37°C for 3
minutes at a shear rate of 10,800 s- . In order to evaluate candidate substances, prior to the
induction of platelet aggregation, 598.8 tl of PRP was treated with 1.2 tl of 25 tM candidate
substance and incubated at 37°C for 3 minutes using a thermomixer. After applying the
shear stress, 20 pl of PRP was fixed in 280 l of a suspension buffer containing 0.5%
glutaraldehyde (134 mM NaCl, 2.9 mM KCl, 1.0 mM MgC2-6H 2 0, 10.0 mM HEPES, 5.0
mM dextrose, 12.0 mM NaHCO 3 , 0.34 mM Na 2HPO4, 0.3% BSA, pH 7.4). Then, the
number of single platelets in the suspension was counted using a hemacytometer. The
degree of inhibition by the candidate substance was calculated according to the following
formula (1). The degree of inhibition was determined by the method described below.
No shear stress-applied group served as a control, and only shear stress-applied group served
as positive control.
Formula 1
Degree of inhibition (%) = [(1-A/B) X 100]/ [(1-A/C) X 100]
A: Number of single platelets in the shear stress-applied sample after treatment with
candidate substance
B: Number of single platelets in the control group with no shear stress applied
C: Number of single platelets in the positive control group with only shear stress
applied
[Table 2]
Platelet aggregation inhibitory effect of candidate substances in PRP
Example Degree of inhibition (%, Mean SEM)
1 23 2 12 25 6 13 26 6 14 34 5 15 24 8 20 30 5 23 28 3
As shown in Table 2 above, it was confirmed that the effect of inhibiting shear stress
induced platelet aggregation was 30% or more in Example 14 and Example 20 (each 25 gM).
In addition, it was confirmed that the inhibitory effect was 20 to 30% in Example 1, Example
12, Example 13, Example 15, and Example 23 (each 25 gM).
1-2. Measurement of platelet aggregation inhibitory effect using human washed
platelets (WP)
To separate human washed platelets (WP), blood was collected from the veins of
healthy males using acid-citrate-dextrose (ACD) as an anticoagulant. At the time of blood
collection, platelet activation was inhibited by treatment with 1 M of prostaglandin E1
(PGE1 ). The collected blood was centrifuged at 150 g for 15 minutes to obtain PRP from
the supernatant, which was centrifuged at 500 g for 10 minutes to obtain platelets. The
platelets were suspended in and washed with a washing buffer (134 mM NaCl, 2.9 mM KCl,
1.0 mMMgCl 2 .6H2 0, 10.0 mM HEPES, 5.0 mM dextrose, 12.0 mM NaHCO 3 , 0.34 mM
Na2HPO4 , 10 % ACD, 0.3 % bovine serum albumin, 1 gM PGE 1, pH 7.4), and then re
centrifuged at 400 g for 10 minutes. The platelets thus obtained were suspended in the suspension buffer. The number of platelets in WP were counted using a hemacytometer.
The platelets were diluted with the suspension buffer so as to include 3 x 108 platelets per 1
ml, and CaCl2 was added to give a final concentration of 2 mM and then used in the
experiments. vWF was added to WP to give a final concentration of 10 pg/ml. WP was
put on a cone-plate viscometer, and shear stress was applied to the WP at 37°C for 3 minutes
at a shear rate of 10,800 s- . In order to evaluate efficacy of candidate substances, prior to
the induction of platelet aggregation, WP was treated with 10, 25, and 50 gM of candidate
substances and incubated at 37°C for 3 minutes using a thermomixer. After applying the
shear stress, 20 pl of WP was fixed in 280 l of the suspension buffer containing 0.5%
glutaraldehyde. Then, the number of single platelets in the suspension was counted using a
hemacytometer. The degree of inhibition by the candidate substance was calculated
according to formula (1). No shear stress-applied group served as control, and only shear
stress-applied group served as a positive control.
[Table 3]
Platelet aggregation inhibitory effect of candidate substances in WP
Example Degree of inhibition (%, Mean SEM)
10LM 4 3.5 1 25 pM 23 1.2 50 pM 27 1.7 10LM 10 2.1 12 25 pM 30 0.9 50 tM 33 2.1 10 pM 12 3.8 13 25 pM 29 4.1 50 pM 34 2.7 14 10 pM 8 1.5
25 pM 27 2.3 50 pM 39 0.6 10 pM 14 2.5 15 25 pM 26 4.0 50 pM 36 3.2 10 pM 18 1.5 20 25 pM 42 4.2 50 pM 46 2.1
As shown in Table 3 above, it was confirmed that Example 1, Example 12, Example
13, Example 14, Example 15 and Example 20 inhibited shear stress-induced platelet
aggregation in WP in a dose-dependent manner.
Experimental Example 2: Evaluation of drug efficacy in arterial thrombosis model
Vehicle (DMSO: Tween 80: DW = 1: 2: 17) or candidate substance (25 mg/kg) was
orally administered to overnight-fasted male Sprague-Dawley rats (250 to 300 g). 30
minutes after administration, the rats were anesthetized by intraperitoneal injection of
urethane (1.25 g/kg). The anesthetized animals were restratined on the operating table, and
the body temperature was maintained using a heating pad during the entire operating
procedure. An incision was made around the neck of the animals to carefully expose the
right carotid artery, and the adipose tissues attached to the blood vessels were carefully
removed. Doppler flow probe (0.5 mm-diameter, MAO.5PSB, Transonic System Inc., USA)
was fixed to the exposed carotid artery, and a doppler flow-meter (TS420, Transonic System
Inc., USA) was connected thereto. 60 minutes after oral administration, a piece of Whatman
No. 1 filter paper (2 mm x 1 mm) soaked with 50% FeCl 3 solution was attached to the
underlying blood vessels to which the probe was fixed. The filter paper was removed after
minutes, and the change of blood flow due to thrombus formation in the carotid artery was measured for 60 minutes after the time point of removal. The occlusion time was defined as the time at which the blood flow became zero more than one minute for the first time.
[Table 4]
Thrombogenesis inhibitory effect of candidate substances
Example Time of thrombogenesis (second) Fold (vs. Control) A Control 356 38 1 936 120 2.6 12 665 77 1.9 13 752 69 2.1 14 615 54 1.7 15 816 78 2.3 20 2122 265 6.0 23 674 92 1.9
As shown in Table 4 above, it was confirmed that the candidate substances exhibiting
the effect of 2.5 times or more as compared with the control in the iron chloride (FeCl3 )
induced thrombogenesis model are Example 1 and Example 20.
Experimental Example 3: Measurement of thrombosis inhibitory effect of candidate
substances in the carotid artery shear stress model
Vehicle (0.5% methylcellulose), clopidogrel (8 mg/kg), aspirin (50 mg/kg) or a
candidate substance was orally administered to male Sprague-Dawley rats (250 to 300 g). 2
hours after administration, the rats were anesthetized by ketamine/rompun (ketamine/xylazine)
cocktail 0.1 ml/100 g. Except for the normal control group, the right cervical skin of the
experimental animals was incised to expose the common carotid artery. A surgical tube
with a length of 1 mm and an inside diameter of 0.58 mm was inserted into the exposed carotid artery and tied with a single thread. The exposed site and the operation site were treated with an anti-adhesion agent, and then sutured for the animals to recover. After the surgery, vehicle, clopidogrel, aspirin or a candidate substance was orally administered to the rats twice a day for 3 days. On the fourth day, 2 hours after the final administration, urethane (100 mg/300 l/100 g) was administered intraperitoneally to the rats to induce anesthesia, and the operation site was opened to separate a total of 1 cm of the blood vessel, 5 mm above and 5 mm below the surgical tube. The separated blood vessel was perfused with
0.2 ml of 0.9% saline at 0.3 ml/min to remove the remaining blood, and then maintained in 1
ml of protein lysis buffer (NaOH 2 g, Na 2 CO 3 0.1 g in 500 ml D.W). After collected, the
blood vessel thrombus was double-boiled in boiling water together with the protein lysis
buffer. 200 l of the reaction solution (10 ml bicinchoninic acid solution + 200 pl 4%
aqueous solution of copper sulfate) was added to 10 tl of the heated thrombus, and the
mixture was reacted at 37°C for 30 minutes and quantified with an ELISA reader (562 nm).
[Table 5]
Thrombosis inhibitory effect of candidate substances in the carotid artery shear stress model
Substance Dose (mg/kg) Operation Amount of thrombus administered (mg, Mean+SEM) Normal C. x 0.005 0.002 Negative C. - o 0.124 0.007 Clopidogrel 8 0 0.067 0.004 Aspirin 50 0 0.092 0.007 Example 1 25 0 0.065 0.005 Example 12 25 0 0.069 0.007 Example 13 25 0 0.064 0.006 Example 14 25 0 0.066 0.006 Example 15 25 0 0.070 0.006 Example 20 25 0 0.068 + 0.005 Example 23 25 0 0.071 + 0.006
As shown in Table 5 above, it was confirmed that in the animals each orally
administered with Example 1, Example 12, Example 13, Example 14, Example 15, Example
, and Example 23, the shear stress-induced thrombogenesis was significantly, remarkably
inhibited compared with the control group. This suggested that the degree of inhibition of
the candidate substances against the thrombogenesis is as good as comparable to that of
clopidogrel when compared with the group administered with clopidogrel, which is the most
commonly used antiplatelet agent.
Formula 2
Degree of inhibition (%) = 100 - [(C - A) X 100 / (B - A)]
A: Amount of thrombus in Normal Control
B: Amount of thrombus in Negative Control
C: Amount of thrombus in candidate substance treatment
Experimental Example 4: Measurement of inhibitory effect of candidate substances for
chemical agonist (physiological agonist)-induced platelet aggregation
To investigate whether the candidate substance has inhibition selectivity for shear
stress-induced platelet aggregation, which is by a physical stimulus, the inhibitory effect of
the candidate substance was investigated in is experiement was conducted by activating
platelets with physiological agonists-i.e., thrombin, collagen and ADP-to study the
inhibitory effect of the candidate substance.
Human PRP (598.8 Il) was treated with 1.2 l of the candidate substance per
concentration (25, 100, 250 pM) and reacted at 37°C for 3 minutes using a thermomixer.
Then, PRP (495 pl) was put in the aggregometer cuvette and preincubated for 1 minute,
followed by treatment with platelet aggregation-inducing reagent, thrombin (0.6-0.8 U/ml), collagen (2-5 pig/ml), or ADP (adenosine diphosphate, 15-20 pM) at the minimum concentration causing maximum aggregation. The degree of aggregation of the platelets was measured by a turbidity change using a lumi-aggregometer (Chrono-Log Co., USA).
The turbidity of the PRP was considered as 0%, and the turbidity of the PPP was considered
as 100%. During the measurement, the reaction mixture was continuously stirred at 1,000
rpm with a silicone-coated magnetic stir bar. The reaction was observed for 5 minutes for
thrombin or ADP, and 6 minutes for collagen.
[Table 6]
Results of measurement of the degree of aggregation by thrombin
Example Degree of platelet aggregation (%, Mean+SEM) Thrombin 83.5 6.5 25 pM 88.0 2.1 1 100 IM 88.7 6.1 250 pM 78.7 1.8 25 tM 99.5 7.5 12 100 IM 95.0 12.0 250 pM 88.5 4.5 25 pM 92.5 5.5 13 100 IM 95.0 12.0 250 pM 88.5 4.5 25 tM 81.3 2.5 14 100 IM 84.0 0.6 250 pM 86.0 4.6 25 tM 95.5 3.5 15 100 IM 100.5 4.5 250 pM 98.0 3.0 25 pM 84.0 3.2 20 100 IM 82.3 3.7 250 pM 82.0 15.0 25 tM 96.0 4.0 23 100 IM 88.5 6.5 250 pM 93.5 1.5
DTI' 2 pM 11.5 1.2 1) DTI: Direct Thrombin Inhibitor
As shown in Table 6 above, it was confirmed that when compared with the group
treated with thrombin only, the candidate substances did not show the platelet aggregation
inhibitory effect up to 250 pM. In contrast, it was confirmed that the platelet aggregation
was inhibited when the positive control DTI was treated.
[Table 7]
Results of measurement of the degree of aggregation by collagen
Example Degree of platelet aggregation (%, Mean+SEM) Collagen 82.6 1.2 25 tM 84.3 3.5 1 100 pM 80.7 10.2 250 pM 84.3 3.8 25 pM 83.0 4.0 12 100 pM 80.0 * 2.0 250 pM 87.5 * 3.5 25 tM 90.0 * 3.0 13 100 tM 79.5 0.5 250 pM 85.5 3.5 25 pM 82.0 1.7 14 100 pM 80.0 * 1.7 250 pM 92.0 * 2.0 25 pM 86.0 * 0.0 15 100 pM 84.5 4.5 250 pM 83.5 3.5 25 tM 82.3 5.8 20 100 pM 81.3 * 3.5 250 pM 87.7 * 2.0 25 pM 82.0 * 5.0 23 100 tM 84.5 4.5 250 pM 83.5 2.5
As shown in Table 7 above, it was confirmed that when compared with the group
treated with collagen only, the candidate substances did not show the platelet aggregation
inhibitory effect up to 250 pM.
[Table 8]
Results of measurement of the degree of aggregation by ADP
Example Degree of platelet aggregation (%, Mean+SEM) ADP 76.0 1.3 25 pM 77.5 3.5 1 100 IM 69.0 6.0 250 pM 78.0 * 7.0 25 tM 76.0 * 3.0 12 100 IM 67.5 * 2.5 250 pM 77.0 12.0 25 pM 75.5 1.5 13 100 IM 75.0 * 1.0 250 pM 71.5 * 6.5 25 tM 74.5 * 2.5 14 100 IM 75.0 * 3.0 250 pM 63.5 5.5 25 pM 70.5 2.5 15 100 pM 68.5 3.5 250 pM 67.0 * 4.0 25 tM 73.0 * 2.0 20 100 IM 69.0 * 1.0 250 pM 66.5 2.5 25 tM 73.5 1.5 23 100 pM 66.0 1.0 250 pM 65.0 * 0.0 Clopidogrel 40 pM 18.3 3.4
As shown in Table 8 above, it was confirmed that when compared with the group
treated with ADP only, the candidate substances did not show the platelet aggregation
inhibitory effect up to 250 pM. In contrast, it was confirmed that the platelet aggregation was inhibited when the positive control clopidogrel was treated.
Experimental Example 5: Evaluation of cytotoxicity of candidate substances
-1. Evaluation of cytotoxicity of candidate substances using EA.hy926 cell line
Experiments were conducted to determine the cytotoxicity of candidate substances in
human vascular endothelial cells (EA.hy926). EA.hy926 was passaged in DMEM
(Dulbecco's Minimum Essential Medium) supplemented with 10% fetal bovine serum (FBS)
at 5% C0 2/37°C. The cells were cultured in a 96 well plate atlx10 4 cells/well for 48 hours,
washed twice with DMEM and then cultured for 24 hours. Candidate substances were
prepared at final concentrations of 25 and 100 pM, applied to the wells at 200 tl per well and
cultured for 24 hours. MTT assay was used to measure the absorbance at 570 nm after
colorization in violet.
[Table 9]
Results of evaluation of cytotoxicity of candidate substances in the EA.hy926 cell line
Example Concentration (tM) Cell viability (%) 25 92.2 2.8 100 94.2 1.9 25 95.1 1.9 12 100 97.2 2.8 25 100.1 1.9 13 100 94.2 2.0 25 99.6 1.7 14 100 99.5 1.6 25 100.8 2.5 15 100 94.9 3.3 25 99.7 3.2 20 100 97.7 2.2
25 104.3 1.8 23 100 99.9 1.9
As shown in Table 9 above, it was confirmed that the candidate substances did not
show toxicity up to 100 pM in the Ea.hy926 cell line.
-2. Evaluation of cytotoxicity of candidate substances using human platelets
Leakage of lactate dehydrogenase (LDH) from the platelets was measured by a
spectro-photometry method. 1.2 pl of the test substance was added to 598.8 pl of PRP, and
the mixture was reacted at 37°C for 3 minutes using a thermomixer. After the reaction, 100
Il of the sample was centrifuged at 12,000 g for 2 minutes, and 80 l of the supernatant was
taken and refrigerated until evaluation. The evaluation was performed within 24 hours.
The control group (positive control) was treated with 50 pM digitonin for 1 hour. 25 pl of
the sample was added to 1ml of a pre-warmed Tris-EDTA NADH solution (56 mM
Tris(hydroxymethyl) aminomethane, 5.6 mM EDTA, 0.17mM p-NADH pH 7.4) and reacted
for 5 minutes at 37°C. Then, 100 pl of a 14 mM pyruvate solution previously heated at
37°C was added to the reaction mixture, and absorbance was immediately measured at a
wavelength of 339 nm for 1 minute using a spectrophotometer (UV-Vis spectrophotometer,
UV-2201, Shidamadzu, Japan). The rate of decrease in absorbance means the rate of
oxidation of NADH, indicating the activity of LDH liberated from platelets. Total activity
of LDH was measured by inducing lysis of platelets with 0.3% Triton X-100. The basal
level of LDH (Control) was measured in plasma. The activity of each sample was measured
as a percentage of the total activity of LDH.
[Table 10]
Results of evaluation of cytotoxicity of candidate substances in platelets
Example LDH leakage (%,MeanSEM) Digitonin 50 pM 80.4 * 1.7 25 tM 2.7 0.5 1 100 tM 2.4 0.2 250 tM 2.7 0.5 25 pM 2.3 * 0.5 12 100 pM 3.6 * 0.1 250 pM 3.6 * 0.8 25 pM 2.2 * 0.4 13 100 pM 4.0 * 1.2 250 tM 4.0 0.3 25 pM 4.8 0.2 14 100 pM 5.6 0.9 250 pM 4.2 0.9 25 pM 2.7 * 0.1 15 100 pM 3.2 * 0.4 250 tM 3.1 1.3 25 pM 4.1 0.7 20 100 pM 5.2 0.4 250 tM 3.5 1.2 25 pM 1.8 * 0.1 23 100 pM 2.2 * 1.3 250 pM 3.2 * 0.5
As shown in Table 10 above, it was confirmed that the candidate substances did not
show toxicity up to 250 pM in the platelets.
-3. Evaluation of cytotoxicity of candidate substances using human liver cells
Experiments were conducted to evaluate cytotoxicity in human liver cells (HepG2).
HepG2 cells, which are human liver carcinoma cell lines, were cultured in DMEM
(Dulbecco's minimum essential medium) supplemented with 10% FBS (fetal bovine serum)
and 1% Penicillin/Streptomycin at 37°C and 5% Co 2 . The cells were cultured in a 48 well
plate at 4x104 cells/well for 24 hours and then used in the experiments. The HepG2 cells were treated with the candidate substances (250 pM) for 18 hours, and then the medium was removed and WST-1 was added, followed by shading for 3 hours for reaction. After3hours, the supernatant was taken and absorbance was measured at 450 nm. Cell viability was calculated by comparing the absorbance measured after adding WST-1 to HepG2 cells not treated with the candidate substances. Acetaminophen (40 mM) was used as a control.
[Table 11]
Results of evaluation of cytotoxicity of 250 pM of candidate substances in HepG2 cell line
Example Cell vaibility (%) Acetaminophen 35.3 3.5 1 91.7 2.0 12 89.0 2.3 13 98.3 5.5 14 87.3 2.7 15 89.7 2.3 20 87.7 2.6 23 82.7 5.5
As shown in Table 11 above, it was confirmed that the candidate substances did not
show hepatotoxicity up to 250 pM in the HepG2 cell line.
Experimental Example 6: Measurement of plasma coagulation time
In order to separate plasma, blood was collected with 3.2% sodium citrate as an
anticoagulant. Whole blood was centrifuged at 2000 g for 20 minutes to obtain plasma.
After treating the plasma with the test substances for 3 minutes, plasma coagulation time was
measured. For plasma coagulation time, Activated Partial Thromboplastin Time (aPTT) and
Prothrombin Time (PT) were measured using BBL@ Fibrometer (Becton Dickinson,
Cockeysville, MD). For measurement of aPTT, the plasma was treated with aPTT reagents in fibrometer cup and reacted at 37°C for 3 min. After the reaction, CaC12 was added and blood coagulation time was measured immediately. For the measurement of PT, PT reagent was added to warmed plasma, and blood coagulation time was measured immediately. DTI, known to prolong plasma coagulation time, was used as a control.
[Table 12]
Results of measurement of plasma coagulation time - aPTT
Example Time (sec) Control 25.5 * 0.8 25 M 23.8 * 1.9 1 100 pM 24.8 * 2.0 250 pM 26.7 0.8 25 pM 24.3 0.1 12 100 pM 26.7 1.0 250 pM 27.2 2.0 25 pM 24.7 * 1.0 13 100 pM 26.6 * 1.8 250 pM 27.5 * 1.7 25 .M 27.0 0.4 14 100 pM 26.7 0.2 250 pM 26.3 1.7 25 gM 26.3 * 2.3 15 100 pM 26.6 * 1.0 250 pM 29.3 * 0.5 25 pM 24.9 1.0 20 100 pM 25.3 0.6 250 pM 25.8 0.9 25 pM 26.2 0.2 23 100 M 29.5 * 1.2 250 pM 26.1 * 0.2 DTI 2 pM 86.6 2.4
As shown in Table 12 above, it was confirmed that the candidate substances did not
significantly change the aPTT points compared with Control, which indicates that the
candidate substances did not affect aPTT.
[Table 13]
Results of measurement of plasma coagulation time - PT
Example Time (sec) Control 10.4 * 0.2 25 pM 10.8 * 0.5 1 100 pM 10.7 * 0.8 250 pM 11.0 0.1 25 pM 10.9 0.1 12 100 pM 11.0 0.5 250 pM 10.5 0.3 25 pM 11.0 * 0.3 13 100 pM 10.6 0.2 250 pM 10.8 * 0.3 25 pM 10.1 0.3 14 100 pM 10.1 0.0 250 pM 11.1 0.1 25 pM 10.7 * 0.0 15 100 M 10.6 * 0.2 250 M 10.9 * 0.1 25 pM 10.8 0.4 20 100 pM 10.2 0.4 2501 M 11.2 0.4 25 pM 10.3 * 0.1 23 100 pM 10.7 * 0.2 250 pM 10.8 * 0.3 DTI 2 pM 47.1 1.8
As shown in Table 13 above, it was confirmed that the candidate substances did not
significantly change the PT points compared with Control, which indicates that the candidate
substances did not affect PT.
Experimental Example 7: Evaluation of bleeding side effect (bleeding time) in
experimental animals
Male Sprague-Dawley rats (250 to 300 g) were fasted overnight and then were orally
administered with the candidate substances at each concentration. After 1 hour, the rats
were anesthetized by intraperitoneal injection of urethane (1.25 g / kg). The 3 mm portion
of the tail tip of the rats was cut and carefully wiped every 30 seconds. Bleeding time was
measured in hours until no more blood was drawn, and when the bleeding lasted longer than
minutes, the bleeding time was recorded as 30 minutes.
[Table 14]
Example Bleeding time (min) Control 6.2 0.4 25 pM 6.0 0.9 1 100 tM 6.5 0.9 25 pM 6.3 0.6 12 100 pM 6.5 0.3 25 pM 6.5 0.6 13 100 pM 7.2 0.3 25 pM 6.7 0.9 14 100 pM 6.3 0.6 25 pM 7.3 0.7 15 100 pM 6.2 0.6 25 pM 6.7 0.6 20 100 pM 7.7 0.4
25 pM 9.5 0.8 Aspirin 100 tM 15.1 0.8 2.5 pM 14.3 1.6 Clopidogrel Clopidogrel 25 pM 26.8 1.6
As shown in Table 14 above, bleeding, which is expected to be a side effect of the
candidate substances, was found to be lower than that of clopidogrel and aspirin as control substances. It was confirmed that all of the compounds of the Examples did not show side effects of bleeding.
Experimental Example 8: Evaluation of bleeding side effect by repeated administration
Candidate substances (50 mg/kg), clopidogrel (15 mg/kg), or aspirin (100 mg/kg)
was each orally administered to ICR mouse (male, 35 to 40 g) once daily for 7 days. One
hour after the last administration, the mice were anesthetized by breathing, and the 4 mm
portion from the tail tip of the mice was cut. Then, the tail tip of the mice was immersed in
a transparent 15-ml tube containing the pre-prepared 37°C saline. The time when blood was
not spread any more and the bleeding stopped was measured.
[Table 15]
Example Dose (mg/kg) Bleeding time (min) Control - 1.6 0.3 Clopidogrel 15 35.4 2.9 Aspirin 100 12.3 0.7 Example 13 50 1.6 0.4 Example 14 50 1.6 0.3
As shown in Table 15 above, the time taken to stop bleeding at the clinical dose
exceeded 35 minutes in the case of clopidogrel, and thus the bleeding time was delayed by
about 22 times compared with the control group. In the case of aspirin, the time taken to
stop bleeding exceeded 12 minutes, and thus the bleeding time was delayed by about 7.6
times. However, when the compounds of Example 13 and Example 14 were repeatedly
administered once a day for 7 days, the time taken to stop bleeding was almost the same as
that of the control, and the bleeding time was about 1 minute and 30 seconds. Therefore,
almost no bleeding side effect was observed for the candidate substances, and it was
confirmed that the candicate substances are a new antiplatelet agent candidate that overcomes the bleeding side effect problem of the existing antiplatelet agents.
Experimental Example 9: 2-week repeat-dose toxicity study
After oral administration of vehicle (0.5% methylcellulose) or the candidate
substances at low dose, medium dose, and high dose (100, 300, 1000 mg/kg) to ICR mice
(female, male, 18 to 26 g) once a day for 2 weeks, the NOAEL values of the candidate
substances were calculated by observing and recording mortality, body weight change,
clinical observations, food and drinking water consumption, gross necropsy findings,
histopathological evaluation of abnormal organ, and organ weights.
[Table 16]
Example NOAEL (No observed adverse effect level) Example 13 > 1000 mg/kg Example 14 > 1000 mg/kg
As shown in Table 16 above, when the compounds of Example 13 or Example 14
were orally administered at doses of 100, 300 and 1000 mg/kg once a day for 2 weeks, no
dead animals were observed, and no abnormal findings were observed in body weight change,
clinical observations, food and drinking water consumption, gross necropsy findings, and
organ weights. Therefore, it was confirmed that the NOAEL value of the candidate
substances might be 1000 mg/kg or more.
Experimental Example 10: Statistics
The significance of the test results was assessed as significant when p was 0.05 or
less via the Student's t-test and the one-way ANOVA test.

Claims (6)

Claims:
1. A compound, which is selected from the following group:
(6,7-Dihydrothieno[3,2-c]pyridin-5(4H)-yl)(3,4-dihydroxypheny)methanone;
(3,4-Dihydroxyphenyl)(4-(5-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)methanone;
N-((4-(4-Fluorobenzyl)morpholin-2-yl)methyl)-3,4-dihydroxybenzamide;
3,4-Dihydroxy-N-(2-oxotetrahydrothiophen-3-yl)benzamide;
N,N'-(Nonan-1,9-diyl)bis(3,4-dihydroxybenzamide);
(4-((4-Chlorophenyl)(pyridin-2-yl)methoxy)piperidin-1-yl)(3,4
dihydroxyphenyl)methanone;
(S)-(4-((4-Chlorophenyl)(pyridin-2-yl)methoxy)piperidin-1-yl)(3,4
dihydroxyphenyl)methanone;
(S)-Methyl-2-(3,4-dihydroxybenzamido)-3-(1H-indol-3-yl)propanoate;
4-(3,4-Dihydroxybenzamido)-1-methyl-3-propyl-1H-pyrazole-5-carboxamide;
2-Methyl-4-oxo-4H-pyran-3-yl 3,4-dihydroxybenzoate;
(3,4-Dihydroxyphenyl)(4-phenylpiperazin-1-yl)methanone;
(6,7-Dihydrothieno[3,2-c]pyridin-5(4H)-yl)(4-hydroxy-3
methoxyphenyl)methanone;
2-Ethyl-4-oxo-4H-pyran-3-yl 4-hydroxy-3-methoxybenzoate;
2-Methyl-4-oxo-4H-pyran-3-yl 4-hydroxy-3-methoxybenzoate;
4-Hydroxy-3-methoxy-N-(4-methoxy-2-nitrophenyl)benzamide;
4-(4-(4-Hydroxy-3-methoxybenzamido)phenoxy)-N-methylpicolinamide;
4-((4-Chlorophenyl)(pyridin-2-yl)methoxy)piperidin-1-yl)(4-hydroxy-3
methoxyphenyl)methanone;
4-Hydroxy-N-((3-hydroxy-5-(hydroxymethyl)-2-methylpyridin-4-yl)methyl)-3
methoxybenzamide;
(27029751_1):AXG
(6,7-Dihydrothieno[3,2-c]pyridin-5(4H)-yl)(2,5-dihydroxyphenyl)methanone;
(4-((4-Chlorophenyl)(pyridin-2-yl)methoxy)piperidin-1-yl)(2,5
dihydroxyphenyl)methanone;
N-((4-(4-Fluorobenzyl)morpholin-2-yl)methyl)-2,5-dihydroxybenzamide;
(2,5-Dihydroxyphenyl)(4-(5-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)methanone;
N-(3,4-Dimethoxyphenethyl)-2,5-dihydroxybenzamide;
2,5-Dihydroxy-N-(2-(thiophen-2-yl)ethyl)benzamide; and
2,5-Dihydroxy-N-(2-oxotetrahydrothiophen-3-yl)benzamide,
or a pharmaceutically acceptable salt or stereoisomer thereof.
2. A composition for the prevention or treatment of thrombotic diseases, comprising as an
active ingredient a compound according to claim 1, or a pharmaceutically acceptable salt or
stereoisomer thereof.
3. The composition of claim 2, wherein the thrombotic diseases are selected from the
group consisting of pulmonary embolism, thrombotic phlebitis, deep vein thrombosis, portal
thrombosis, angina pectoris, arteriosclerosis and cerebral infarction.
4. A method of prevention or treatment of thrombotic diseases associated with shear
stress-induced platelet aggregation in a subject in need thereof, the method comprising
administering to the subject a therapeutically effective amount of a compound of claim 1 or a
pharmaceutically acceptable salt or stereoisomer thereof.
5. Use of a compound of claim 1 or a pharmaceutically acceptable salt or stereoisomer
thereof in the manufacture of a medicament for prevention or treatment of thrombotic diseases
associated with shear stress-induced platelet aggregation in a subject in need thereof.
6. The method of claim 4 or the use of claim 5, wherein the thrombotic diseases are
(27029751_1):AXG selected from the group consisting of pulmonary embolism, thrombotic phlebitis, deep vein thrombosis, portal thrombosis, angina pectoris, arteriosclerosis and cerebral infarction.
Shin Poong Pharmaceutical Co., Ltd.
Patent Attorneys for the Applicant/Nominated Person
SPRUSON&FERGUSON
(27029751_1):AXG
AU2016317968A 2015-09-04 2016-09-02 Compound having effect of inhibiting platelet aggregation and salt thereof, and composition for preventing or treating thrombotic diseases, containing same Active AU2016317968B2 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
KR10-2015-0125270 2015-09-04
KR20150125270 2015-09-04
PCT/KR2016/009859 WO2017039395A1 (en) 2015-09-04 2016-09-02 Compound having effect of inhibiting platelet aggregation and salt thereof, and composition for preventing or treating thrombotic diseases, containing same

Publications (2)

Publication Number Publication Date
AU2016317968A1 AU2016317968A1 (en) 2018-03-29
AU2016317968B2 true AU2016317968B2 (en) 2021-03-25

Family

ID=58188978

Family Applications (1)

Application Number Title Priority Date Filing Date
AU2016317968A Active AU2016317968B2 (en) 2015-09-04 2016-09-02 Compound having effect of inhibiting platelet aggregation and salt thereof, and composition for preventing or treating thrombotic diseases, containing same

Country Status (16)

Country Link
US (1) US10730886B2 (en)
EP (1) EP3345910B1 (en)
JP (1) JP7013375B2 (en)
KR (1) KR102209441B1 (en)
CN (1) CN108602837B (en)
AU (1) AU2016317968B2 (en)
BR (1) BR112018004249A2 (en)
CA (1) CA2997549C (en)
IL (1) IL257809B (en)
MX (1) MX2018002575A (en)
MY (1) MY192720A (en)
NZ (1) NZ740520A (en)
PH (1) PH12018500433A1 (en)
RU (1) RU2739915C2 (en)
WO (1) WO2017039395A1 (en)
ZA (1) ZA201802065B (en)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112669687B (en) * 2020-12-01 2022-06-21 大连理工大学 Method for manufacturing personalized in-vitro interlayer physical model
KR20240056417A (en) 2022-10-21 2024-04-30 고려대학교 산학협력단 Novel 1-benzyl-3-phenyl-1H-pyrazole derivatives and pharmaceutical use thereof
KR20240056386A (en) 2022-10-21 2024-04-30 고려대학교 산학협력단 Novel N-phenyl-4-((4-phenylpiperazin-1-yl)methyl)benzamide derivatives and pharmaceutical use thereof

Citations (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2899437A (en) * 1959-08-11 Pyridylethylated salicylamides
EP0251143A1 (en) * 1986-06-23 1988-01-07 Bristol-Myers Squibb GmbH 2-Oxo-1-[[(Substituted Sulfonyl)Amino]-Carbonyl]Azetidines
US4725598A (en) * 1983-09-13 1988-02-16 Kureha Kagaku Kogyo Kabushiki Kaisha Derivative of dihydroxybenzamide and a pharmaceutical composition having an anti-inflammatory activity
US5523421A (en) * 1993-11-16 1996-06-04 Pacific Corporation Kojic acid derivatives
WO2005013489A2 (en) * 2003-07-31 2005-02-10 Qualcomm Incorporated Delay matching for clock distribution in a logic circuit
WO2010023161A1 (en) * 2008-08-25 2010-03-04 Boehringer Ingelheim International Gmbh Aryl- and heteroarylcarbonyl derivatives of substituted nortropanes, medicaments containing such compounds and their use
EP2412701A1 (en) * 2009-03-25 2012-02-01 Ajinomoto Co., Inc. Novel amide derivative and skin whitening agent
WO2012155812A1 (en) * 2011-05-13 2012-11-22 上海特化医药科技有限公司 Processes for the preparation of roflumilast and intermediates thereof
WO2013087834A2 (en) * 2011-12-16 2013-06-20 Syntivia Cosmetic composition for stimulating the cellular anti-aging functions of the skin
WO2014070983A1 (en) * 2012-10-31 2014-05-08 The Regents Of The University Of Michigan Plasminogen activator-1 inhibitors and methods of use thereof
EP2762134A1 (en) * 2013-02-04 2014-08-06 Bioversys AG Composition for treatment of pathogens that are resistant to tetracyclines
WO2015050379A1 (en) * 2013-10-01 2015-04-09 광주과학기술원 Novel quinolinone derivative and use thereof
WO2017019772A1 (en) * 2015-07-27 2017-02-02 Sanford Burnham Prebys Medical Discovery Institute Modulators of myocyte lipid accumulation and insulin resistance and methods of use thereof

Family Cites Families (27)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2848335A (en) * 1954-03-25 1958-08-19 Eastman Kodak Co Stabilization of normally oxidizable materials with hydroxybenzamide compounds
GB1343916A (en) * 1972-05-31 1974-01-16 Pierrel Spa Compounds of the azaspirane series
ES8704252A1 (en) * 1985-06-28 1987-03-16 Asea Stal Ab Multi-bed fluid bed boiler.
JPH01291242A (en) * 1988-05-18 1989-11-22 Tosoh Corp Positive type photoresist composition containing novel photosensitive agent
US5244890A (en) * 1988-06-06 1993-09-14 Fujisawa Pharmaceutical Co., Ltd. Cephem compounds
CA2076012A1 (en) * 1990-02-14 1991-08-15 Yasuyuki Kato Agent for inhibiting the formation of denatured ldl
US5281623A (en) * 1990-08-27 1994-01-25 Eli Lilly And Company Method for treating inflammation
US5280046A (en) * 1991-02-22 1994-01-18 The University Of Colorado Foundation, Inc. Method of treating type I diabetes
EP0613879A4 (en) * 1991-05-20 1995-05-03 Tsumura & Co Phellodendrine analogs and allergy type iv suppressor containing the same as active ingredient.
EP0641770B1 (en) * 1993-03-17 1998-05-13 Meiji Seika Kabushiki Kaisha Novel compound with platelet aggregation inhibitor activity
GB9313285D0 (en) * 1993-06-28 1993-08-11 Zeneca Ltd Acid derivatives
JP5278983B2 (en) * 1999-11-17 2013-09-04 塩野義製薬株式会社 New uses of amide compounds
US20090124690A1 (en) * 2000-04-03 2009-05-14 Alberte Randall S Generation of Combinatorial Synthetic Libraries and Screening for Novel Proadhesins and Nonadhesins
TW591020B (en) * 2001-06-20 2004-06-11 Wyeth Corp 6-(aryl-amido or aryl-amidomethyl)-naphthalen-2-yloxy-acidic derivatives as inhibitors of plasminogen activator inhibitor type-1 (PAI-1)
SI1511710T1 (en) * 2002-05-31 2014-04-30 Proteotech, Inc. Compounds, compositions and methods for the treatment of amyloid diseases and synucleinopathies such as alzheimer s disease, type 2 diabetes, and parkinson s disease
WO2005051913A1 (en) * 2003-11-28 2005-06-09 Sankyo Company, Limited Cyclic amine derivative having heteroaryl ring
JP2006273839A (en) * 2005-03-04 2006-10-12 National Institute Of Advanced Industrial & Technology Adiponectin production promotor
JP5246834B2 (en) * 2005-12-27 2013-07-24 独立行政法人産業技術総合研究所 Adiponectin production enhancer
JP2009537556A (en) * 2006-05-18 2009-10-29 アリーナ ファーマシューティカルズ， インコーポレイテッド Acetamide derivatives as modulators of 5-HT2A serotonin receptors useful for the treatment of disorders associated with 5-HT2A serotonin receptors
US20120101087A1 (en) * 2007-12-12 2012-04-26 Alberte Randall S Generation of Combinatorial Synthetic Libraries and Screening for Novel Proadhesins and Nonadhesins
WO2009078423A1 (en) * 2007-12-18 2009-06-25 National University Corporation University Of Toyama Fused tricyclic compound having aldose reductase inhibitory activity
CN101648919A (en) * 2008-08-13 2010-02-17 中国医学科学院药物研究所 3-substituted salicylamide compound, preparation method, medicinal composition and application thereof
EP2364086B1 (en) * 2008-11-20 2016-09-14 Glsynthesis Inc. Novel antithrombotic diadenosine tetraphosphates and related analogs
WO2010060854A1 (en) * 2008-11-25 2010-06-03 Nerviano Medical Sciences S.R.L. Bicyclic pyrazole and isoxazole derivatives as antitumor and antineurodegenerative agents
WO2012025638A1 (en) * 2010-08-27 2012-03-01 Universität des Saarlandes Selective 17beta-hydroxysteroid dehydrogenase type 1 inhibitors
JPWO2012042621A1 (en) * 2010-09-29 2014-02-03 味の素株式会社 Salt enhancer
WO2014022343A1 (en) * 2012-08-01 2014-02-06 Bristol-Myers Squibb Company 7-hydroxy-indolinyl antagonists of p2y1 receptor

Patent Citations (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2899437A (en) * 1959-08-11 Pyridylethylated salicylamides
US4725598A (en) * 1983-09-13 1988-02-16 Kureha Kagaku Kogyo Kabushiki Kaisha Derivative of dihydroxybenzamide and a pharmaceutical composition having an anti-inflammatory activity
EP0251143A1 (en) * 1986-06-23 1988-01-07 Bristol-Myers Squibb GmbH 2-Oxo-1-[[(Substituted Sulfonyl)Amino]-Carbonyl]Azetidines
US5523421A (en) * 1993-11-16 1996-06-04 Pacific Corporation Kojic acid derivatives
WO2005013489A2 (en) * 2003-07-31 2005-02-10 Qualcomm Incorporated Delay matching for clock distribution in a logic circuit
WO2010023161A1 (en) * 2008-08-25 2010-03-04 Boehringer Ingelheim International Gmbh Aryl- and heteroarylcarbonyl derivatives of substituted nortropanes, medicaments containing such compounds and their use
EP2412701A1 (en) * 2009-03-25 2012-02-01 Ajinomoto Co., Inc. Novel amide derivative and skin whitening agent
WO2012155812A1 (en) * 2011-05-13 2012-11-22 上海特化医药科技有限公司 Processes for the preparation of roflumilast and intermediates thereof
WO2013087834A2 (en) * 2011-12-16 2013-06-20 Syntivia Cosmetic composition for stimulating the cellular anti-aging functions of the skin
WO2014070983A1 (en) * 2012-10-31 2014-05-08 The Regents Of The University Of Michigan Plasminogen activator-1 inhibitors and methods of use thereof
EP2762134A1 (en) * 2013-02-04 2014-08-06 Bioversys AG Composition for treatment of pathogens that are resistant to tetracyclines
WO2014118361A1 (en) * 2013-02-04 2014-08-07 BioVersys AG Composition for treatment of pathogens that are resistant to tetracyclines
WO2015050379A1 (en) * 2013-10-01 2015-04-09 광주과학기술원 Novel quinolinone derivative and use thereof
WO2017019772A1 (en) * 2015-07-27 2017-02-02 Sanford Burnham Prebys Medical Discovery Institute Modulators of myocyte lipid accumulation and insulin resistance and methods of use thereof

Non-Patent Citations (38)

* Cited by examiner, † Cited by third party
Title
CAS Registry Number 1030528-04-1, STN entry date 25 Jun 2008 *
CAS Registry Number 1049136-81-3, STN entry date 14 September 2008 *
CAS Registry Number 1204916-56-2, STN entry date 09 Feb 2010 *
CAS Registry Number 1204918-08-0, STN entry date 09 Feb 2010 *
CAS Registry Number 1204951-11-0, STN entry date 09 February 2010 *
CAS Registry Number 1204953-50-3, STN entry date 09 Feb 2010 *
CAS Registry Number 1205211-63-7, STN entry date 10 February 2010 *
CAS Registry Number 1205469-73-3, STN entry date 10 Feb 2010 *
CAS Registry Number 1205471-73-3, STN entry date10 Feb 2010 *
CAS Registry Number 1205501-86-5, STN entry date 10 Feb 2010 *
CAS Registry Number 1205502-72-2, STN entry date 10 Feb 2010 *
CAS Registry Number 1205860-99-6, STN entry date 11 Feb 2010 *
CAS Registry Number 1309259-73-1, STN entry date 13 Jun 2011 *
CAS Registry Number 1638343-39-1, STN entry date 10 December 2014 *
CAS Registry Number 1690723-58-0, STN entry date 25 April 2015 *
CAS Registry Number 1786146-62-0, STN entry date 22 Jun 2015 *
CAS Registry Number 1786146-72-2, STN entry date 22 Jun 2015 *
CAS Registry Number 1787735-48-1, STN entry date24 Jun 2015 *
CAS Registry Number 1789283-42-6, STN entry date 26 Jun 2015 *
CAS Registry Number 1789287-05-3, STN entry date 26 Jun 2015 *
CAS Registry Number 1789654-44-9, STN entry date 26 Jun 2015 *
CAS Registry Number 1789948-21-5, STN entry date 28 June 2015 *
Cas Registry Number 1790098-32-6 , STN entry date 28 June 2015 *
CAS Registry Number 328011-42-3, STN entry date 19 Mar 2001 *
CHAPADO, L. et al., "Synthesis and Evaluation of the Platelet Antiaggregant Properties of Phenolic Antioxidants Structurally Related to Rosmarinic Acid", Bioorganic Chemistry, (2010-06), vol. 38, no. 3, pages 108 - 114 *
GIOVANNI MARZARO ET AL, "Using the TOPS-MODE approach to fit multi-target QSAR models for tyrosine kinases inhibitors", EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, vol. 46, no. 6, (2011-02-28), pages 2185 - 2192 *
HELVETICA CHIMICA ACTA, (2009-06-01), vol. 92, no. 6, pages 1126 - 1133 *
HUDSON, R.A., et. al., Simplified Catechin-Gallate Inhibitors of HIV-1 Reverse Transcriptase, Bioorganic & Medicinal Chemistry Letters (2001), Volume 11, issue 20, pages 2763-2767 *
JAE B. PARK, "Becatamide Found in Houttuynia cordataSuppresses P-selectin Expression Via Inhibiting COX Enzyme, Not Increasing cAMP in Platelets", PHYTOTHERAPY RESEARCH, (2015-06-26), vol. 29, pages 1381 - 1387 *
LI, G. et al., "Ligustrazinyl Amides: a Novel Class of Ligustrazine Phenolic Acid Derivatives with Neuroprotective Effects", Chemistry Central Journal, (2015-03-04), vol. 9, no. 9 *
LI, X. H., ET AL, "A new phenolic lactone from the bark of Phellodendron chinese", Chinese Chem. Lett., (2009), Volume 20, pages 958-960 *
PAN, S., et al., "Synthesis and biological activity of tyrosine protein kinase inhibitors", Acta Pharmaceutica Sinica, (1997), Volume 32, Issue 7, pages 515-523 *
SCHUBERT H ET AL, "SYNTHESE UND OXYDATION VON UNSYMMETRISCH VERBRUECKTEN DIHYDROCHINONEN", JOURNAL FÜR PRAKTISCHE CHEMIE (1977-01-01), vol. 319, no. 5, pages 745 - 754 *
ST JOHN S. ET AL, "Design, synthesis, biological and structural evaluation of functionalized resveratrol analogues as inhibitors of quinone reductase 2", BIOORGANIC & MEDICINAL CHEMISTRY, (2013-07-27), vol. 21, no. 19, pages 6022- 6037 *
WANG, H., ET AL, "Chemical Studies on Iridoids form Picrorhiza scrophulariiflora", Chin. J. Nat. Med., (2006), Volume 4, Issue 1, pages 36-39 *
WASSIER, K., et. al., Synthesis and antifungal evaluation of hydroxy-3-phenyl-2H-1,3-benzoxazine-2,4(3H)-diones and their thioanalogs, Journal of Heterocyclic Chemistry (2009), Volume 46, Issue 5, pages 873-880 *
YU K-L ET AL, "Novel quinolizidine salicylamide influenza fusion inhibitors", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, (1999-08-02), vol. 9, no. 15, pages 2177 - 2180 *
ZHANG, H., ET AL., "Lamiridosins, Hepatitis C Virus Entry Inhibitors form Lamium album" J. Nat. Prod. (2009), Volume 72, pages 2158-2162 *

Also Published As

Publication number Publication date
PH12018500433A1 (en) 2018-08-29
EP3345910B1 (en) 2023-11-01
ZA201802065B (en) 2019-01-30
WO2017039395A1 (en) 2017-03-09
US10730886B2 (en) 2020-08-04
US20180251472A1 (en) 2018-09-06
IL257809A (en) 2018-04-30
EP3345910A1 (en) 2018-07-11
JP7013375B2 (en) 2022-01-31
KR20170028858A (en) 2017-03-14
NZ740520A (en) 2022-07-29
EP3345910A4 (en) 2019-09-11
CN108602837A (en) 2018-09-28
RU2739915C2 (en) 2020-12-29
EP3345910C0 (en) 2023-11-01
KR102209441B1 (en) 2021-01-29
IL257809B (en) 2022-04-01
JP2018534344A (en) 2018-11-22
CA2997549C (en) 2023-10-03
MY192720A (en) 2022-09-05
RU2018111712A3 (en) 2020-02-05
MX2018002575A (en) 2018-07-06
CN108602837B (en) 2022-02-11
AU2016317968A1 (en) 2018-03-29
CA2997549A1 (en) 2017-03-09
RU2018111712A (en) 2019-10-07
BR112018004249A2 (en) 2018-12-04

Similar Documents

Publication Publication Date Title
ES2382979T3 (en) Ether derivative of ligustrazine aromatic acid, its method of preparation, pharmaceutical composition and application
AU2016317968B2 (en) Compound having effect of inhibiting platelet aggregation and salt thereof, and composition for preventing or treating thrombotic diseases, containing same
AU776053B2 (en) Diazepan derivatives or salts thereof
US4243669A (en) 2-Substituted benzisothiazolones
CN116082303A (en) Novel oxopyridines, intermediates and uses thereof
WO2009157020A1 (en) Coumarin compounds for the treatment of cardiovascular diseases and process for preparing the same
JP2005533762A (en) Novel tetrahydroisoquinoline enantiomer compound and pharmaceutically acceptable salt thereof, process for producing the same and pharmaceutical composition containing the same
CN107400131A (en) Eliquis derivative and its production and use
US5206428A (en) Tetrahydronaphthalene derivatives and preparation thereof
WO2009150668A1 (en) Dihydropyridimidinone compounds for the treatment of cardiovascular diseases and process for preparing the same
CN112047931B (en) FXIa coagulation factor inhibitor, pharmaceutical composition and application thereof
TW200526642A (en) Heterocyclic derivatives
MX2007001566A (en) Antiplatelet agent and process for producing the same.
CN101812025B (en) Pyrazine aromatic acid ester compound, preparation method and medical application
JP7339698B2 (en) Antithrombotic composition containing Noseri extract and antithrombotic agent
JP2002526531A (en) Benzamide derivatives as thrombin inhibitors
CN105085345B (en) MENTHOL class P2Y12 receptor antagonist containing nitro and application thereof
CN105085347B (en) MENTHOL class P2Y12 receptor antagonist of one class nitrile group-containing and application thereof
Tamboli Design, Synthesis and Antiplatelet Activity of Some Heterocyclic Compounds
KR100512184B1 (en) Novel enantiomers of tetrahydroisoquinoline derivatives and their pharmaceutically acceptable salts, their preparations and pharmaceutical compositions
CN105085346B (en) MENTHOL class P2Y12 receptor antagonist of amino-contained and application thereof
CN102199150A (en) Optical active oxazolidinone derivatives as well as preparation methods and application to preparing medicaments
JPH05178814A (en) Medicine composition
CN106800524A (en) Compound, preparation method and its usage of one class containing bishydrazide and naphthyl structure

Legal Events

Date Code Title Description
FGA Letters patent sealed or granted (standard patent)